Heteroaryl substituted spiropiperidinyl derivatives and pharmaceutical uses thereof

ABSTRACT

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; 
     
       
         
         
             
             
         
       
     
     wherein R 1  R 2 , R 4  and X 1  are defined herein, a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. non-provisional application which claimspriority to European patent application No. 20191191.4 filed on Aug. 14,2020; the content of which is incorporated by reference in its entirety

The present invention relates to novel heteroaryl substitutedspiropiperidinyl compounds useful as inhibitors of leukotriene C4synthase (LTC4S). The present invention also relates to pharmaceuticalcompositions comprising said compounds, methods of using said compoundsin the treatment of various diseases and disorders, and processes forpreparing the said novel compounds.

FIELD OF THE INVENTION

The present invention relates to compounds of formula (I) orpharmaceutically acceptable salts thereof, and to their use ininhibiting LTC4S. Hence the compounds of the invention may be useful inthe treatment of diseases and/or disorders related to LTC4S. Suchdiseases and/or disorders typically include respiratorydiseases/disorders, inflammation and/or disease/disorders having aninflammatory component. The present invention further relates topharmaceutical compositions comprising said heteroaryl substitutedspiropiperidinyl compounds of formula (I), methods of using saidcompounds in the treatment of various diseases and disorders, andprocesses for preparing the said novel compounds.

BACKGROUND OF THE INVENTION

The cysteinyl leukotrienes (cys-LTs), leukotriene C4 (LTC4) and itsmetabolites, LTD4 and LTE4, are proinflammatory lipid mediators inasthma and other inflammatory diseases. They are generated through the5-lipoxygenase/LTC4 synthase (LTC4S) pathway and act via at least twodistinct G protein-coupled receptors. Leukotriene (LT) C₄ synthase(LTC4S) catalyzes the conjugation reaction between the fatty acid LTA₄and GSH to form the pro-inflammatory LTC₄ an important mediator ofasthma.

There are many diseases/disorders that are inflammatory in their natureor have an inflammatory component. One of the major problems associatedwith existing treatments of inflammatory conditions is a lack ofefficacy and/or the prevalence of side effects. Asthma is a chronicinflammatory disease affecting 6% to 8% of the adult population of theindustrialized world. In children, the incidence is even higher, beingclose to 10% in most countries. Asthma is the most common cause ofhospitalization for children under the age of fifteen. Treatmentregimens for asthma depend upon the severity of the condition. Mildcases are either untreated or are only treated with inhaled P-agonists.Patients with more severe asthma are typically treated withanti-inflammatory compounds on a regular basis.

There is a considerable under-treatment of asthma, which is due at leastin part to perceived risks with existing maintenance therapy (mainlyinhaled corticosteroids). These include risks of growth retardation inchildren and loss of bone mineral density, resulting in unnecessarymorbidity and mortality. As an alternative to steroids, LTRAs have beendeveloped. These drugs may be given orally, but are considerably lessefficacious than inhaled steroids and usually do not control airwayinflammation satisfactorily. This combination of factors has led to atleast 50% of all asthma patients being inadequately treated.

A similar pattern of under-treatment exists in relation to allergicdisorders, where drugs are available to treat a number of commonconditions but are underused in view of apparent side effects. Forinstance, rhinitis, conjunctivitis and dermatitis may have an allergiccomponent, but may also arise in the absence of underlying allergy.Indeed, nonallergic conditions of this class are in many cases moredifficult to treat.

Other inflammatory disorders which may be mentioned include: chronicobstructive pulmonary disease (COPD) is a common disease affecting 6% to8% of the world population. The disease is potentially lethal, and themorbidity and mortality from the condition is considerable. At present,there is no known pharmacological treatment capable of changing thecourse of COPD; pulmonary fibrosis (this is less common than COPD, butis a serious disorder with a very poor prognosis); inflammatory boweldisease (a group of disorders with a high morbidity rate—today onlysymptomatic treatment of such disorders is available); rheumatoidarthritis and osteoarthritis (common disabling inflammatory disorders ofthe joints—there are currently no curative, and only moderatelyeffective symptomatic, treatments available for the management of suchconditions); diabetes, a disease affecting over 3% of the worldpopulation, and growing, causing considerable morbidity and mortality;and cardiovascular disease.

Inflammation is also a common cause of pain. Inflammatory pain may arisefor numerous reasons, such as infection, surgery or other trauma.Moreover, several malignancies have inflammatory components adding tothe symptomatology of the patients. Inflammation may also play a role incancer with leukotrienes involved in cancer cell proliferation andextending cancer cell lifetimes. Thus, new and/or alternative treatmentsfor respiratory and/or inflammatory disorders would be of benefit to allof the above-mentioned patient groups. In particular, there is a realand substantial unmet clinical need for an effective anti-inflammatorydrug capable of treating inflammatory disorders, in particular asthmaand atopic dermatitis, with no real or perceived side effects.

The inhibition of LTC4S may therefore be useful in the treatment of thecys-LT relevant inflammatory diseases such as asthma, allergic rhinitis,atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis,chronic obstructive pulmonary disease.

For reviews on cysteinyl leukotrienes and LTC4 see B. Lam et al.Clinical and Experimental Allergy Reviews, 2004, 4, 89-95; B. Lam etal., Prostaglandins & Other Lipid Mediators, 2002, 68-69, 511-520; H.-E.Claesson et al., Journal of Internal Medicine 1999, 245, 205-277

SUMMARY OF THE INVENTION

There remains a need for new treatments and therapies for diseases ordisorders related to LTC4S. The invention provides compounds,pharmaceutically acceptable salts thereof, pharmaceutical compositionsthereof and combinations thereof, which compounds are LTC4S inhibitors.The invention further provides methods of treating, preventing, orameliorating disease and/or disorders related to LTC4S, comprisingadministering to a subject in need thereof an effective amount of anLTC4S inhibitor.

Various embodiments of the invention are described herein.

Within certain aspects, provided herein is a compound of Formula I or apharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is phenyl optionally substituted with one or more halo substituents;

R² is H or fluoro;

X¹ is CH₂ or O;

R⁴ is a mono or bicyclic heteroaryl, optionally substituted with one ormore R³ substituents;

each R³ is independently selected from C₆₋₁₀aryl, benzyl, C₁₋₆alkyl,C₃₋₇cycloalkoxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, halo,haloC₁₋₆alkyl, OR⁵, CN, C(O)OC₁₋₆alkyl, OH, C₃₋₇cycloalkyl,C₃₋₇cycloalkenyl, 5- to 10 membered heteroaryl, 4-10 memberedheterocyclyl, —C(O)NH₂, and NR^(a)R^(b), wherein R^(a) and R^(b) areindependently H, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl-C₁₋₆alkyl orhalo C₁₋₆alkyl;

wherein said aryl, heterocyclyl, heteroaryl, C₃₋₇cycloalkyl,C₃₋₇cycloakenyl, C₃₋₇cycloalkoxy are further optionally substituted withone or more substituents independently selected from OH, CN,C₃₋₇cycloalkyl, C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl),halo, haloC₁₋₆alkyl, —C(O)—C₁₋₆alkyl, phenyl optionally furthersubstituted with halo; and heteroaryl optionally substituted with halo,C₁₋₆alkyl, haloC₁₋₆alkyl or C₃₋₇cycloalkyl;

R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, alkoxyC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, C₃₋₇cycloalkylC₁₋₆alkyl, phenyl,benzyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl;

wherein phenyl, heterocyclyl and C₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆akenyl is optionally substituted by one or moresubstituents selected from C₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyloptionally further substituted with halo; heterocyclyl optionallyfurther substituted with C₁₋₆alkyl or haloC₁₋₆alkyl;

with the proviso that when R² is F, then X¹ is CH₂.

In another aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound according tothe definition of formula (I), or a pharmaceutically acceptable saltthereof, or subformulae thereof and one or more pharmaceuticallyacceptable carriers. The pharmaceutical composition is useful in thetreatment of diseases and/or disorders related to LTC4S activity.

In another aspect, the invention provides a combination, in particular apharmaceutical combination, comprising a therapeutically effectiveamount of the compound according to the definition of formula (I), or apharmaceutically acceptable salt thereof, or subformulae thereof and oneor more therapeutic agent.

Another aspect of the present invention relates to method of modulationLTC4S activity, more particularly inhibiting LTC4S activity. The methodcomprises administering to a subject in need thereof a compound ofFormula (I) or subformulae thereof, or a pharmaceutically acceptablesalt thereof.

Another aspect of the invention relate to method of treating a diseaseor a disorder selected from: respiratory diseases/disorders,inflammation and/or disease/disorders having an inflammatory component,for example allergic disorders, asthma, childhood wheezing, chronicobstructive pulmonary disease, aspirin exacerbated respiratory disease,bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease(e.g. sarcoidosis, pulmonary fibrosis, scleroderma lung disease, andusual interstitial in pneumonia), ear nose and throat diseases (e.g.sinusitis, rhinitis, nasal polyposis, rhinosinusitis, otitis media, andallergic eosinophilic esophagitis), eye diseases (e.g. conjunctivitisand giant papillary conjunctivitis), skin diseases (e.g. psoriasis,atopic dermatitis, eczema and chronic urticaria), rheumatic diseases(e.g. rheumatoid arthritis, arthrosis, psoriasis arthritis,osteoarthritis, systemic lupus erythematosus, systemic sclerosis),vasculitis (e.g. Henoch-Schonlein purpura, Loffler's syndrome andKawasaki disease), cardiovascular diseases (e.g. atherosclerosis,cerebrovascular diseases, acute ischemic heart attacks and post-heartattack treatment), gastrointestinal diseases (e.g. eosinophilic diseasesin the gastrointestinal system, inflammatory bowel disease, irritablebowel syndrome, colitis, celiaci and gastric haemorrhagia), urologicdiseases (e.g. glomerulonephritis, interstitial cystitis, nephritis,nephropathy, nephrotic syndrome, hepatorenal syndrome, andnephrotoxicity), diseases of the central nervous system (e.g. cerebralischemia, spinal cord injury, migraine, multiple sclerosis, andsleep-disordered breathing), endocrine diseases (e.g. autoimmunethyreoiditis, diabetes-related inflammation), urticaria, anaphylaxis,angioedema, oedema in Kwashiorkor, dysmenorrhoea, burn-induced oxidativeinjury, multiple trauma, pain (inflammatory and neuropathic), endotoxinshock, sepsis, bacterial infections (e.g. from Helicobacter pylori,Pseudomonas aerugiosa or Shigella dysenteriae), fungal infections (e.g.vulvovaginal candidasis), viral infections (e.g. hepatitis, meningitis,parainfluenza and respiratory syncytial virus), hypereosinofilicsyndrome, and malignancies (e.g. Hodgkin's lymphoma, leukemia (e.g.eosinophil leukemia and chronic myelogenous leukemia), mastocytos,polycytemi vera, and ovarian carcinoma).

In particular, compounds of the invention may be useful in treatingallergic disorders, asthma, aspirin exacerbated respiratory disease(AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergicrhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilicgastrointestinal diseases and inflammatory bowel disease. In oneparticular embodiment, compounds of the invention are useful in treatingasthma. In another particular embodiment, compounds of the invention areuseful in the treatment of atopic dermatitis or chronic urticaria.

Another aspect of the invention relates the use of a compound of Formula(I), or subformulae thereof, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment of adisease or a disorder selected from respiratory diseases/disorders,inflammation and/or disease/disorders having an inflammatory component,for example allergic disorders, asthma, childhood wheezing, chronicobstructive pulmonary disease, aspirin exacerbated respiratory disease,bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease(e.g. sarcoidosis, pulmonary fibrosis, scleroderma lung disease, andusual interstitial in pneumonia), ear nose and throat diseases (e.g.sinusitis, rhinitis, nasal polyposis, rhinosinusitis, otitis media, andallergic eosinophilic esophagitis), eye diseases (e.g. conjunctivitisand giant papillary conjunctivitis), skin diseases (e.g. psoriasis,atopic dermatitis, eczema and chronic urticaria), rheumatic diseases(e.g. rheumatoid arthritis, arthrosis, psoriasis arthritis,osteoarthritis, systemic lupus erythematosus, systemic sclerosis),vasculitis (e.g. Henoch-Schonlein purpura, Loffler's syndrome andKawasaki disease), cardiovascular diseases (e.g. atherosclerosis,cerebrovascular diseases, acute ischemic heart attacks and post-heartattack treatment), gastrointestinal diseases (e.g. eosinophilic diseasesin the gastrointestinal system, inflammatory bowel disease, irritablebowel syndrome, colitis, celiaci and gastric haemorrhagia), urologicdiseases (e.g. glomerulonephritis, interstitial cystitis, nephritis,nephropathy, nephrotic syndrome, hepatorenal syndrome, andnephrotoxicity), diseases of the central nervous system (e.g. cerebralischemia, spinal cord injury, migraine, multiple sclerosis, andsleep-disordered breathing), endocrine diseases (e.g. autoimmunethyreoiditis, diabetes-related inflammation), urticaria, anaphylaxis,angioedema, oedema in Kwashiorkor, dysmenorrhoea, burn-induced oxidativeinjury, multiple trauma, pain (inflammatory and neuropathic), endotoxinshock, sepsis, bacterial infections (e.g. from Helicobacter pylori,Pseudomonas aerugiosa or Shigella dysenteriae), fungal infections (e.g.vulvovaginal candidasis), viral infections (e.g. hepatitis, meningitis,parainfluenza and respiratory syncytial virus), hypereosinofilicsyndrome, and malignancies (e.g. Hodgkin's lymphoma, leukemia (e.g.eosinophil leukemia and chronic myelogenous leukemia), mastocytos,polycytemi vera, and ovarian carcinoma).

The present disclosure also provides a compound of formula I, orsubformulae thereof, or a pharmaceutical acceptable salt thereof, foruse in the treatment of a disease or disorder selected from respiratorydiseases/disorders, inflammation and/or disease/disorders having aninflammatory component, for example allergic disorders, asthma,childhood wheezing, chronic obstructive pulmonary disease, aspirinexacerbated respiratory disease, bronchopulmonary dysplasia, cysticfibrosis, interstitial lung disease (e.g. sarcoidosis, pulmonaryfibrosis, scleroderma lung disease, and usual interstitial inpneumonia), ear nose and throat diseases (e.g. sinusitis, rhinitis,nasal polyposis, rhinosinusitis, otitis media, and allergic eosinophilicesophagitis), eye diseases (e.g. conjunctivitis and giant papillaryconjunctivitis), skin diseases (e.g. psoriasis, atopic dermatitis,eczema and chronic urticaria), rheumatic diseases (e.g. rheumatoidarthritis, arthrosis, psoriasis arthritis, osteoarthritis, systemiclupus erythematosus, systemic sclerosis), vasculitis (e.g.Henoch-Schonlein purpura, Loffler's syndrome and Kawasaki disease),cardiovascular diseases (e.g. atherosclerosis, cerebrovascular diseases,acute ischemic heart attacks and post-heart attack treatment),gastrointestinal diseases (e.g. eosinophilic diseases in thegastrointestinal system, inflammatory bowel disease, irritable bowelsyndrome, colitis, celiaci and gastric haemorrhagia), urologic diseases(e.g. glomerulonephritis, interstitial cystitis, nephritis, nephropathy,nephrotic syndrome, hepatorenal syndrome, and nephrotoxicity), diseasesof the central nervous system (e.g. cerebral ischemia, spinal cordinjury, migraine, multiple sclerosis, and sleep-disordered breathing),endocrine diseases (e.g. autoimmune thyreoiditis, diabetes-relatedinflammation), urticaria, anaphylaxis, angioedema, oedema inKwashiorkor, dysmenorrhoea, burn-induced oxidative injury, multipletrauma, pain (inflammatory and neuropathic), endotoxin shock, sepsis,bacterial infections (e.g. from Helicobacter pylori, Pseudomonasaerugiosa or Shigella dysenteriae), fungal infections (e.g. vulvovaginalcandidasis), viral infections (e.g. hepatitis, meningitis, parainfluenzaand respiratory syncytial virus), hypereosinofilic syndrome, andmalignancies (e.g. Hodgkin's lymphoma, leukemia (e.g. eosinophilleukemia and chronic myelogenous leukemia), mastocytos, polycytemi vera,and ovarian carcinoma).

DETAILED DESCRIPTION OF THE INVENTION

The invention therefore provides a compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is phenyl optionally substituted with one or more halo substituents;

R² is H or fluoro;

X¹ is CH₂ or O;

R⁴ is a mono or bicyclic heteroaryl, optionally substituted with one ormore R³ substituents;

each R³ is independently selected from C₆₋₁₀aryl, benzyl, C₁₋₆alkyl,C₃₋₇cycloalkoxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, halo,haloC₁₋₆alkyl, OR⁵, CN, C(O)OC₁₋₆alkyl, OH, C₃₋₇cycloalkyl,C₃₋₇cycloalkenyl, 5- to 10 membered heteroaryl, 4-10 memberedheterocyclyl, —C(O)NH₂, and NR^(a)R^(b), wherein R^(a) and R^(b) areindependently H, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl-C₁₋₆alkyl orhalo C₁₋₆alkyl;

wherein said aryl, heterocyclyl, heteroaryl, C₃₋₇cycloalkyl,C₃₋₇cycloakenyl, C₃₋₇cycloalkoxy are further optionally substituted withone or more substituents independently selected from OH, CN,C₃₋₇cycloalkyl, C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, hydroxyC₁₋₆alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl),halo, haloC₁₋₆alkyl, —C(O)—C₁₋₆alkyl, phenyl optionally furthersubstituted with halo; and heteroaryl optionally substituted with halo,C₁₋₆alkyl, haloC₁₋₆alkyl or C₃₋₇cycloalkyl;

R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, alkoxyC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, C₃₋₇cycloalkylC₁₋₆alkyl, phenyl,benzyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl;

wherein phenyl, heterocyclyl and C₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆akenyl is optionally substituted by one or moresubstituents selected from C₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyloptionally further substituted with halo; heterocyclyl optionallyfurther substituted with C₁₋₆alkyl or haloC₁₋₆alkyl;

with the proviso that when R² is F, then X¹ is CH₂.

Unless specified otherwise, the term “compounds of the presentinvention” refers to compounds of formula (I) and subformulae thereof,and salts thereof, as well as all stereoisomers (includingdiastereoisomers and enantiomers), rotamers, tautomers and isotopicallylabeled compounds (including deuterium substitutions), as well asinherently formed moieties.

For purpose of the interpreting this specification, the followingdefinitions will apply unless specified otherwise and whetherappropriate, terms used in the singular will also include the plural andvice versa.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “thecompound” includes reference to one or more compounds; and so forth.

Definitions

As used herein, the term “C₁₋₆alkyl” refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, containing no unsaturation, having from one to six carbon atoms,and which is attached to the rest of the molecule by a single bond. Theterm “C₁₋₂alkyl” is to be construed accordingly. Examples of C₁₋₆alkylinclude, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl and 1,1-dimethylethyl (f-butyl).

As used herein, the term “C₁₋₆alkoxy” refers to a radical of the formula—OR_(a) where R_(a) is a C₁₋₆alkyl radical as generally defined above.Examples of C₁₋₆alkoxy include, but are not limited to, methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

As used herein, the term “C₃₋₇cycloalkyl” refers to a stable mono- orbicyclic saturated hydrocarbon radical consisting solely of carbon andhydrogen atoms, having from three to seven carbon atoms. C₃₋₆cycloalkylis to be construed the same way. Cycloalkyl groups can include bridgedrings as well as spirocyclic rings. Examples of C₃₋₇cycloalkyl include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl.

“Halogen” refers to bromo, chloro, fluoro or iodo.

As used herein, the term “haloC₁₋₆alkyl” refers to C₁₋₆alkyl radical, asdefined above, substituted by one or more halo radicals, as definedabove. Examples of halogenC₁₋₆alkyl include, but are not limited to,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl and1,4,4-trifluorobutan-2-yl.

As used herein, the term “haloC₁₋₆alkoxy” refers to C₁₋₆alkoxy radical,as defined above, substituted by one or more halo radicals, as definedabove. Examples of haloC₁₋₆alkyl include, but are not limited to,trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, and2,2,2-trifluoroethoxy.

As used herein, the term “heterocyclyl” refers to a heterocyclic groupthat is saturated or partially saturated and is preferably a monocyclicor a polycyclic ring (in case of a polycyclic ring particularly abicyclic, tricyclic or spirocyclic ring); and has 3 to 24, morepreferably 4 to 16, most preferably 5 to 10 and most preferably 5 or 6ring atoms; wherein one or more, preferably one to four, especially oneor two ring atoms are a heteroatom (the remaining ring atoms thereforebeing carbon). The term heterocyclyl excludes heteroaryl. Theheterocyclic group can be attached at a heteroatom or a carbon atom. Theheterocyclyl can include fused or bridged rings as well as spirocyclicrings.

In one embodiment, the herterocyclyl is a 5-7 monocyclic ring containing1 or 2 heteroatoms. In another embodiment, the heterocyclyl is a 6-10spiroheterocyclyl. Examples of heterocycles include dihydrofuranyl,dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine,dihydropyranyl, oxathiolanyl, dithiolane, oxathianyl, thiomorpholino,oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanyl, oxathianyl,thiepanyl, azepanyl, dioxepanyl, and diazepanyl. A non limiting exampleof a spiroheterocyclyl is azaspiro[2.3]hexanyl. A non limiting exampleof a bridged heterocyclic ring is bicyclo[1.1.1]pentanyl.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic-ring system, having 1 to 8 heteroatoms. Eachheteroatoms is independently selected from O, N or S wherein S and N maybe oxidized to various oxidation states. Typically, the heteroaryl is a5-10 membered ring system (e.g., 5- or 6-membered monocycle or an 8-10membered bicycle).

Typically a monocyclic heteroaryl contains from 5 or 6 ring membersselected from carbon atoms and 1 to 4 heteroatoms, and. Typicalmonocyclic heteroaryl groups include thienyl, furyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxa-2,3-diazolyl,oxa-2,4-diazolyl, oxa-2,5-diazolyl, oxa-3,4-diazolyl, thia-2,3-diazolyl,thia-2,4-diazolyl, thia-2,5-diazolyl, thia-3,4-diazolyl, 3-, 4-, or5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or5-1,2,4-triazolyl, 4- or 5-1,2, 3-triazolyl, tetrazolyl, 2-, 3-, or4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-,4-, or 5-pyrimidinyl.

When the heteroaryl is substituted with a hydroxyl group, the compoundsmay exist in various tautomeric form. One non limiting example oftautomerisation is the following:

As used herein, the term “aryl” refers to an aromatic hydrocarbon grouphaving 6-20 carbon atoms in the ring portion. Typically, aryl ismonocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms.Non-limiting examples include phenyl, naphthyl. In a preferredembodiment, aryl is phenyl.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments of thepresent invention.

In embodiment 1, the invention provides a compound of the formula (I),or a pharmaceutically acceptable salt thereof, as described above.

In embodiment 2, the invention provides a compound of the formula (I),or a pharmaceutically acceptable salt thereof, according to embodiment1, wherein R⁴ is selected from the group consisting of pyrimidinyl,pyrazinyl, triazolyl, triazinyl, pyridinyl, pyridine oxide, pyrimidineoxide, pyrazine oxide, quinolinyl, quinazolinyl, quinoxalinyl,indazolyl, pyrazolopyrimidinyl, pyridopyrazinyl, triazolopyridazinyl,benzooxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, oxazolyl, andthiazolyl, each of which is optionally substituted with one or more R³substituents;

each R³ is independently selected from C₆₋₁₀aryl, benzyl, C₁₋₆alkyl,C₃₋₇cycloalkoxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, halo,haloC₁₋₆alkyl, OR⁵, CN, C(O)OC₁₋₆alkyl, OH, C₃₋₇cycloalkyl,C₃₋₇cycloalkenyl, 5- to 10 membered heteroaryl, 4-10 memberedheterocyclyl, —C(O)NH₂, and NR^(a)R^(b), wherein R^(a) and R^(b) areindependently H, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl-C₁₋₆alkyl orhalo C₁₋₆alkyl;

wherein said aryl, heterocyclyl, heteroaryl, C₃₋₇cycloalkyl,C₃₋₇cycloakenyl, C₃₋₇cycloalkoxy are further optionally substituted withone or more substituents independently selected from OH, CN,C₃₋₇cycloalkyl, C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl),halo, haloC₁₋₆alkyl, —C(O)—C₁₋₆alkyl, phenyl optionally furthersubstituted with halo; and heteroaryl optionally substituted with halo,C₁₋₆alkyl, haloC₁₋₆alkyl or C₃₋₇cycloalkyl; and wherein

R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, alkoxyC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, C₃₋₇cycloalkylC₁₋₆alkyl, phenyl,benzyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl;

wherein phenyl, heterocyclyl and C₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆akenyl is optionally substituted by one or moresubstituents selected from C₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyloptionally further substituted with halo; heterocyclyl optionallyfurther substituted with C₁₋₆alkyl or haloC₁₋₆alkyl.

In embodiment 3, the invention provides a compound of Formula (I)according to embodiment 1 or 2, or a pharmaceutically acceptable saltthereof, wherein R⁴ is selected from

wherein the * depicts the point of attachment to the nitrogen of thespiropiperidinyl moiety; and

wherein n is an integer between 1 and 3; p is 1 or 2, s is an integerbetween 1 and 4; and

R^(3a), R^(3b) and R^(3c) are independently selected from the groupconsisting of H, C₆₋₁₀aryl, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN,C(O)OC₁₋₆alkyl, OH, C₃₋₇cycloalkyl, C₃₋₇Cycloalkenyl, 5- to 10 memberedheteroaryl, 4-10 membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b),wherein R^(a) and R^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl;

wherein said aryl, heterocyclyl, heteroaryl, C₃₋₇cycloalkyl,C₃₋₇cycloakenyl, C₃₋₇cycloalkoxy are further optionally substituted withone or more substituents independently selected from OH, CN,C₃₋₇cycloalkyl, C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl),halo, haloC₁₋₆alkyl, —C(O)—C₁₋₆alkyl, phenyl optionally furthersubstituted with halo; and heteroaryl optionally substituted with halo,C₁₋₆alkyl, haloC₁₋₆alkyl or C₃₋₇cycloalkyl;

R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, alkoxyC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, C₃₋₇cycloalkylC₁₋₆alkyl, phenyl,benzyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl;

wherein phenyl, heterocyclyl and C₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆akenyl is optionally substituted by one or moresubstituents selected from C₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyloptionally further substituted with halo; heterocyclyl optionallyfurther substituted with C₁₋₆alkyl or haloC₁₋₆alkyl; and wherein

R^(3d) is selected from H, C₆₋₁₀aryl, C₁₋₆alkyl, haloC₁₋₆alkyl,C₃₋₆cycloalkyl, 5- or 6-membered heteroaryl; and wherein said aryl,cycloalkyl, heteroaryl are further optionally substituted with one ormore substituents independently selected from C₃₋₆cycloalkyl, C₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkoxy, halo and haloC₁₋₆alkyl; or apharmaceutically acceptable salt thereof.

In embodiment 4, the invention pertains to a compound according to anyone of embodiments 1 to 3, wherein the compound has Formula (II):

wherein R^(3a), R^(3b) and R^(3c) are independently selected from thegroup consisting of H, C₆₋₁₀aryl, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN,C(O)OC₁₋₆alkyl, OH, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5- to 10 memberedheteroaryl, 4-10 membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b),wherein R^(a) and R^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl;

wherein said aryl, heterocyclyl, heteroaryl, C₃₋₇cycloalkyl,C₃₋₇cycloakenyl, C₃₋₇cycloalkoxy are further optionally substituted withone or more substituents independently selected from OH, CN,C₃₋₇cycloalkyl, C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl),halo, haloC₁₋₆alkyl, —C(O)—C₁₋₆alkyl, phenyl optionally furthersubstituted with halo; and heteroaryl optionally substituted with halo,C₁₋₆alkyl, haloC₁₋₆alkyl or C₃₋₇cycloalkyl; R⁵ is C₁₋₆alkyl,haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, alkoxyC₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkenyl, C₃₋₇cycloalkylC₁₋₆alkyl, phenyl, benzyl, 4-10 memberedheterocyclyl, 5-10 membered heteroaryl;

wherein phenyl, heterocyclyl and C₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆akenyl is optionally substituted by one or moresubstituents selected from C₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyloptionally further substituted with halo; heterocyclyl optionallyfurther substituted with C₁₋₆alkyl or haloC₁₋₆alkyl; or apharmaceutically acceptable salt thereof.

In a particular aspect of this embodiment, at least one of R^(3a),R^(3b) and R^(3c) is not hydrogen.

In embodiment 5, the invention relates to compound of Formula (II), or apharmaceutically acceptable salt thereof, wherein R^(3a) is H; NH₂ orhydroxyC₁₋₃alkyl;

R^(3b) is selected from the group consisting of halo, C₁₋₆alkyl,haloC₁₋₆alkyl, C₃₋₇cycloalkyl, OR⁵, 4-10 membered heterocyclyl, 5- to10-membered heteroaryl, phenyl, and wherein said heterocyclyl,heteroaryl, phenyl and cycloalkyl is further optionally substituted withone or more substituents independently selected from C₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkoxy, halo and haloC₁₋₆alkyl; wherein

R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cycloalkyl, phenyl, benzyl, 4-10membered heterocyclyl, 5-10 membered heteroaryl;

wherein phenyl, heterocyclyl or C₃₋₇cycloakyl is optionally substitutedby one or more substituents independently selected from C₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkoxy, halo; and

R^(3c) is H or halo.

In another aspect of embodiment 5, the invention relates to compound ofFormula (II), or a pharmaceutically acceptable salt thereof, whereinR^(4a) is H or NH₂, —CH₂OH;

R^(3b) is selected from the group consisting of halo, C₁₋₆alkyl,haloC₁₋₆alkyl, C₃₋₇cycloalkyl, OR⁵, a 4-10 membered heterocyclylselected from:

wherein R^(3′) is H, C₁₋₆alkyl or haloC₁₋₆alkyl;

or R^(3b) is a 5- to 10-membered heteroaryl selected from:

or

R^(3b) is a phenyl;

wherein said above heterocyclyl, heteroaryl, phenyl and cycloalkyl arefurther optionally substituted with one or more substituentsindependently selected from C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, haloand haloC₁₋₆alkyl;

R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cycloalkyl, phenyl, benzyl, a 4-10membered heterocyclyl selected from:

or R⁵ is a phenyl, a benzyl or a pyridinyl;

wherein cycloalkyl, heterocyclyl, phenyl, benzyl and pyridinyl areoptionally substituted with one or more substituents independentlyselected from halo, C₁₋₆alkyl, haloC₁₋₆alkyl and C₃₋₇alkoxy; and

and R^(4c) is H or halo.

In embodiment 6, the invention relates to a compound according to anyone of embodiments 1 to 3, wherein the compound has Formula (III):

wherein

wherein Y¹ is N or CR^(3c); and wherein R^(3a), R^(3b) and R^(3c) areindependently selected from the group consisting of H, C₆₋₁₀aryl,benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN, C(O)OC₁₋₆alkyl, OH,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5- to 10 membered heteroaryl, 4-10membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b), wherein R^(a) andR^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl;

wherein said aryl, heterocyclyl, heteroaryl, C₃₋₇cycloalkyl,C₃₋₇cycloakenyl, C₃₋₇cycloalkoxy are further optionally substituted withone or more substituents independently selected from OH, CN,C₃₋₇cycloalkyl, C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl),halo, haloC₁₋₆alkyl, —C(O)—C₁₋₆alkyl, phenyl optionally furthersubstituted with halo; and heteroaryl optionally substituted with halo,C₁₋₆alkyl, haloC₁₋₆alkyl or C₃₋₇cycloalkyl;

R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, alkoxyC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, C₃₋₇cycloalkylC₁₋₆alkyl, phenyl,benzyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl;

wherein phenyl, heterocyclyl and C₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆akenyl is optionally substituted by one or moresubstituents selected from C₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyloptionally further substituted with halo; heterocyclyl optionallyfurther substituted with C₁₋₆alkyl or haloC₁₋₆alkyl; or apharmaceutically acceptable salt thereof.

In a particular aspect of this embodiment, at least one of R^(3a),R^(3b) and R^(3c) is not hydrogen.

In one particular aspect of embodiment 6; the invention relates tocompound of Formula (III), or a pharmaceutically acceptable saltthereof, wherein R^(3a), R^(3b) and R^(3c) are independently selectedfrom H, C₆₋₁₀aryl, C₃₋₆cycloalkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, OH,C₃₋₆cycloalkyl, 5- or 6-membered heteroaryl, a 5-10 memberedheterocyclyl and NR^(a)R^(b), wherein R^(a) and R^(b) are independentlyH, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₇cycloalkyl-C₁₋₆alky or haloC₁₋₆alkylor a; and

wherein said aryl, heterocyclyl, heteroaryl, C₃₋₆cycloalkyl,C₃₋₆cycloalkoxy are further optionally substituted with one or moresubstituents independently selected from C₃₋₆cycloalkyl, C₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkoxy, halo and haloC₁₋₆alkyl; or apharmaceutically acceptable salt thereof. In a particular aspect of thisembodiment, when Y¹ is CR^(3c); at least one of R^(3a), R^(3b) andR^(3c) is not hydrogen. In yet another aspect of this embodiment, whenY¹ is N, at least one of R^(3a), and R^(3b) is not hydrogen.

In another aspect of embodiment 6, the invention relates to compound ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Y¹is CR^(3c); R^(3b) and R^(3c) are H; R^(3a) is selected from the groupconsisting of H, halo, haloC₁₋₆alkyl, C₃₋₆cycloalkyl, haloC₁₋₆alkoxy, a5-10 membered heterocyclyl, NR^(a)R^(b), wherein R^(a) and R^(b) areindependently H, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₇cycloalkyl-C₁₋₆alkyl orhaloC₁₋₆alkyl; and wherein said cycloalkyl, heterocyclyl are furtheroptionally substituted with one or more substituents independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, halo andhaloC₁₋₆alkyl.

In another aspect of the embodiment 6, the invention pertains to acompound according to any one of the subembodiments 6, according toFormula (III), or a pharmaceutically acceptable salt thereof, wherein Y¹is CR^(3c).

In another aspect of the embodiment 6, the invention pertains to acompound according to any one of the subembodiments 6, according toFormula (III), or a pharmaceutically acceptable salt thereof, wherein Y¹is N.

In embodiment 7, the invention pertains to a compound according to anyone of embodiments 1 to 3, wherein the compound has Formula (IV), or apharmaceutically acceptable salt thereof;

and wherein

R¹ is as defined in Formula I,

Y² is N or CR^(3b); and wherein

R^(3a), R^(3b), R^(3c) and R^(3e) are independently selected from H,C₆₋₁₀aryl, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN, C(O)OC₁₋₆alkyl, OH,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5- to 10 membered heteroaryl, 4-10membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b), wherein R^(a) andR^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl;

wherein said aryl, heterocyclyl, heteroaryl, C₃₋₇cycloalkyl,C₃₋₇cycloakenyl, C₃₋₇cycloalkoxy are further optionally substituted withone or more substituents independently selected from OH, CN,C₃₋₇cycloalkyl, C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl),halo, haloC₁₋₆alkyl, —C(O)—C₁₋₆alkyl, phenyl optionally furthersubstituted with halo; and heteroaryl optionally substituted with halo,C₁₋₆alkyl, haloC₁₋₆alkyl or C₃₋₇cycloalkyl;

R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, alkoxyC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, C₃₋₇cycloalkylC₁₋₆alkyl, phenyl,benzyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl;

wherein phenyl, heterocyclyl and C₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆akenyl is optionally substituted by one or moresubstituents selected from C₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyloptionally further substituted with halo; heterocyclyl optionallyfurther substituted with C₁₋₆alkyl or haloC₁₋₆alkyl; or apharmaceutically acceptable salt thereof.

In one aspect of embodiment 7, the invention relates to a compoundaccording to Formila (IV) or a pharmaceutically acceptable salt thereof,wherein R^(3a), R^(3b), R^(3c) and R^(3e) are independently selectedfrom H, C₆₋₁₀aryl, C₃₋₆cycloalkoxy, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, OH,C₃₋₆cycloalkyl, 5- or 6-membered heteroaryl, a 5-10 memberedheterocyclyl and NR^(a)R^(b), wherein R^(a) and R^(b) are independentlyH, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₇cycloalkyl-C₁₋₆alkyl or haloC₁₋₆alkyl;and

wherein said aryl, heterocyclyl, heteroaryl, C₃₋₆cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl, C₃₋₆cycloalkoxy are further optionallysubstituted with one or more substituents independently selected fromC₃₋₆cycloalkyl, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, halo andhaloC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof. In aparticular aspect of this embodiment, when Y² is CR^(3b); at least oneof R^(3a), R^(3b), R^(3c) and R^(3e) is not hydrogen. In yet anotheraspect of this embodiment, when Y² is N, at least one of R^(3a), R^(3c)and R^(3d) is not hydrogen. Preferably the pyridine or pyrazine ring issubstituted at the R^(3b) position, (i.e. meta position).

In one aspect of embodiment 7, and subembodiments of embodiment 6, theinvention relates to a compound according to Formula (IV), or apharmaceutically acceptable salt thereof, wherein Y² is CR^(3b).

In another aspect of embodiment 7, and subembodiments of embodiment 6,the invention relates to a compound according to Formula (IV), or apharmaceutically acceptable salt thereof, wherein Y² is N.

In embodiment 8, the invention pertains to a compound according to anyone of embodiments 1 to 3, wherein the compound has Formula (V)

wherein

Y³ is N, NR^(3d) or CR^(3a);

Y⁴ is N, NR^(3f) or CR^(3b);

Y⁵ is N, NR^(3g) or CR^(3c);

Y⁶ is N, NR^(3h) or CR^(3e);

wherein R^(3a), R^(3b), R^(3c), R^(3e) are independently selected fromH, C₆₋₁₀aryl, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN, C(O)OC₁₋₆alkyl, OH,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5- to 10 membered heteroaryl, 4-10membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b), wherein R^(a) andR^(b) are independently H, C₁₋₆alkyl, C₃₋₇Cycloalkyl,C₃₋₇Cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl;

wherein said aryl, heterocyclyl, heteroaryl, C₃₋₇cycloalkyl,C₃₋₇cycloakenyl, C₃₋₇cycloalkoxy are further optionally substituted withone or more substituents independently selected from OH, CN,C₃₋₇cycloalkyl, C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl),halo, haloC₁₋₆alkyl, —C(O)—C₁₋₆alkyl, phenyl optionally furthersubstituted with halo; and heteroaryl optionally substituted with halo,C₁₋₆alkyl, haloC₁₋₆alkyl or C₃₋₇cycloalkyl;

R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, alkoxyC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, C₃₋₇cycloalkylC₁₋₆alkyl, phenyl,benzyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl;

wherein phenyl, heterocyclyl and C₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl,C₃₋₇cycloalkylC₁₋₆akenyl is optionally substituted by one or moresubstituents selected from C₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyloptionally further substituted with halo; heterocyclyl optionallyfurther substituted with C₁₋₆alkyl or haloC₁₋₆alkyl;

wherein R^(3d), R^(3f), R^(3g), R^(3h) are independently selected fromH, C₆₋₁₀aryl, C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₆cycloalkyl, 5- or 6-memberedheteroaryl;

and wherein said aryl, heteroaryl, C₃₋₆cycloalkyl are further optionallysubstituted with one or more substituents independently selected fromC₃₋₆cycloalkyl, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, halo andhaloC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.

The inner circle in the 5 membered ring shown in formula (V) means thatthe ring is an aromatic ring, and hence the members Y³, Y⁴, Y⁵ and/or Y⁶have to be selected accordingly not to violate aromaticity.

In embodiment 9, the invention pertains to a compound according toembodiment 8; or a pharmaceutically acceptable salt thereof, wherein themoiety

is selected from the following:

wherein the * depicts the point of attachment to the nitrogen of thespiropiperidinyl moiety and R^(3a), R^(3b), R^(3c), R^(4e) and R^(4f)are as defined in embodiment 8 and * depicts the point of attachment tothe nitrogen of the spiropiperidinyl moiety.

In some aspect of embodiment 9, R^(3a) is H; R^(3b) or R^(3c) isselected from phenyl optionally substituted with one or more halo;C₁₋₆alkyl; CN, haloC₁₋₆alkyl; C₃₋₆cycloalkyl, a 5-10 memberedheterocyclyl; and NR^(a)R^(b), wherein R^(a) and R^(b) are independentlyH, C₁₋₆alkyl, C₃₋₆cycloalkyl or haloC₁₋₆alkyl; wherein heterocyclyl isoptionally substituted with haloC₁₋₆alkyl or C₁₋₆alkyl; and R^(3f) isphenyl optionally substituted with one or more halo.

In embodiment 10, the invention relates to a compound of any of theprevious embodiment and sub-embodiments (e.g. a compound according toany one of the formulae (I) to (V)), or a pharmaceutically acceptablesalt thereof, wherein R¹ is phenyl optionally substituted with one ortwo substituents independently selected from F and Cl.

In one aspect of embodiment 10, the invention relates to a compoundaccording to embodiment 10, or a pharmaceutically acceptable saltthereof wherein R¹ is selected from:

wherein * depicts the point of attachment of the phenyl to the lactamnitrogen of the spiropiperidinyl moiety.

In embodiment 11, the invention relates to a compound of any of theprevious embodiment and sub-embodiments wherein X¹ is CH₂ and R² is F orH, or a pharmaceutically acceptable salt thereof. In one aspect ofembodiment 11, R² is H. In another aspect of embodiment 11, R² is F; ora pharmaceutically acceptable salt thereof.

In embodiment 12, the invention relates to a compound of any of theprevious embodiment and sub-embodiments wherein X¹ is O and R² is H, ora pharmaceutically acceptable salt thereof.

In embodiment 13, the invention relates to a compound of formula (I),according to embodiment 1, wherein the compound is selected from:

-   1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(6-(trifluoromethyl)benzo[d]oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(4-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine    1-oxide;-   9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(2-(3,3-dimethylazetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-((1R,2R/1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(6-hydroxy-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-cyclopentyl-1,2,4-triazin-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one-   1-(4-chloro-3-fluorophenyl)-9-(4-(trifluoromethyl)pyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(7-(trifluoromethyl)quinazolin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-(4-fluorophenyl)oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(2-phenyl-2H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-cyclohexyloxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)azetidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-(pyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-phenyl-1,3,4-oxadiazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine    1-oxide;-   4-(3-chlorophenoxy)-2-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)pyridine    1-oxide;-   9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(4-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(4-(4-amino-4-(trifluoromethyl)piperidin-1-yl)pyrimidin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-5-fluoro-6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(6-amino-2-(3-hydroxy-3-methylazetidin-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(6-(1,4-oxazepan-4-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-9-(2-amino-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(2-methyl-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(1H-pyrazol-1-yl)pyrimidine-2-carbonitrile;-   1-(3,4-difluorophenyl)-9-(2-methoxy-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(6-(1H-pyrazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(2-morpholino-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(2-(dimethylamino)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(6-(4-chloro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-5-fluoro-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(4-amino-6-(4-fluoro-1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(6-(oxetan-3-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(6-(oxazol-2-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(6-amino-2-(pyridin-2-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one;-   1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one;-   Synthesis    1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one;-   rac-1-(3,4-difluorophenyl)-9-(2-(1-hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one;-   4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carboxamide;-   9-(2-chloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-9-(2-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   (S)-9-(2-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-9-(4-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(6-(4-fluoro-1H-pyrazol-1-yl)-2-morpholinopyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(4,4-difluorocyclohex-1-en-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(4-fluorophenyl-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one;-   9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one;-   9-(2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(2-(hydroxynethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecane-2-one;-   1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(4-chloro-3-fluorophenyl)-9-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(4-propoxypyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-1-(3,4-difluorophenyl)-9-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-chloro-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   (S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   (S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(3,3-difluorocyclobutoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(2,2,2-trifluoroethoxy-1,1-d2)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-isopropoxypyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(2-hydroxyethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-9-(2-amino-6-(2,2,2-trifluoro-1-(3-methyloxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-9-(2-amino-6-((4,4-difluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-9-(2-amino-6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-9-(2-amino-6-((tetrahydro-2H-pyran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-9-(2-amino-6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-9-(2-amino-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-9-(2-amino-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-1-(3,4-difluorophenyl)-9-(6-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-2-(hydroxymethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac-1-(3,4-difluorophenyl)-9-(6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(hydroxymethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   (S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   (S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   (S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   rac ethyl    4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(((3S,4S)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate;-   (R)-9-(2-amino-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;-   (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;-   (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;-   1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;-   (S)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;-   (S)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;-   (R)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;-   rac-9-(2-amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;-   rac-1-(3,4-difluorophenyl)-4-fluoro-9-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;    and-   1-(3,4-difluorophenyl)-4-fluoro-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;    or a pharmaceutically acceptable salt thereof.

In embodiment 14, the invention relates to a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein the compound isselected from

-   1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one;-   (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one,-   (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;-   9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;    and-   9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;    or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the invention relates to a compoundof formula (I), according to embodiment 1, wherein the compound is1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one,or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the invention pertains to a compoundof formula (I), according to embodiment 1, wherein the compound is9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one;or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the invention pertains to a compoundof formula (I), according to embodiment 1, wherein the compound is(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one,or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the invention pertains to a compoundof formula (I), according to embodiment 1, wherein the compound is(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one,or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the invention pertains to a compoundof formula (I), according to embodiment 14, wherein the compound is9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one,or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the invention pertains to a compoundof formula (I), according to embodiment 14, wherein the compound is9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;or a pharmaceutically acceptable salt thereof.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possiblestereoisomers or as mixtures thereof, for example as pure opticalisomers, or as stereoisomer mixtures, such as racemates anddiastereoisomer mixtures, depending on the number of asymmetric carbonatoms. The present invention is meant to include all such possiblestereoisomers, including racemic mixtures, diasteriomeric mixtures andoptically pure forms. Optically active (R)- and (S)-stereoisomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts”. The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

In another aspect, the present invention provides compounds of any oneof formulae (I) to (V) in acetate, ascorbate, adipate, aspartate,benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate,hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate,malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate,naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate,sulfosalicylate, sulfate, tartrate, tosylate trifenatate,trifluoroacetate or xinafoate salt form.

In another aspect, the present invention provides compounds of any oneof formulae (I) to (V) in sodium, potassium, ammonium, calcium,magnesium, iron, silver, zinc, copper, isopropylamine, benzathine,cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazineor tromethamine salt form.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Isotopes that can be incorporated intocompounds of the invention include, for example, isotopes of hydrogen.

Further, incorporation of certain isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index ortolerability. It is understood that deuterium in this context isregarded as a substituent of a compound of the formula (I). Theconcentration of deuterium, may be defined by the isotopic enrichmentfactor. The term “isotopic enrichment factor” as used herein means theratio between the isotopic abundance and the natural abundance of aspecified isotope. If a substituent in a compound of this invention isdenoted as being deuterium, such compound has an isotopic enrichmentfactor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated deuterium atom), at least4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation). Itshould be understood that the term “isotopic enrichment factor” can beapplied to any isotope in the same manner as described for deuterium.

Other examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²³I, ¹²⁴I, ¹²⁵I respectively. Accordingly itshould be understood that the invention includes compounds thatincorporate one or more of any of the aforementioned isotopes, includingfor example, radioactive isotopes, such as ³H and ¹⁴C, or those intowhich non-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically labelled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically-labeled compounds offormula (I) can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

PHARMACEUTICAL COMPOSITION

As used herein, the term “pharmaceutical composition” refers to acompound of the invention, or a pharmaceutically acceptable saltthereof, together with at least one pharmaceutically acceptable carrier,in a form suitable for oral or parenteral administration.

As used herein, the term “pharmaceutically acceptable carrier” refers toa substance useful in the preparation or use of a pharmaceuticalcomposition and includes, for example, suitable diluents, solvents,dispersion media, surfactants, antioxidants, preservatives, isotonicagents, buffering agents, emulsifiers, absorption delaying agents,salts, drug stabilizers, binders, excipients, disintegration agents,lubricants, wetting agents, sweetening agents, flavoring agents, dyes,and combinations thereof, as would be known to those skilled in the art(see, for example, Remington The Science and Practice of Pharmacy,22^(nd) Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviate, inhibit,prevent and/or ameliorate a condition, or a disorder or a disease (i)mediated by LTC4S, or (ii) associated with LTC4S activity, or (iii)characterized by activity (normal or abnormal) of LTC4S; or (2) reduceor inhibit the activity of LTC4S; or (3) reduce or inhibit theexpression of LTC4S. In another non-limiting embodiment, the term “atherapeutically effective amount” refers to the amount of the compoundof the present invention that, when administered to a cell, or a tissue,or a non-cellular biological material, or a medium, is effective to atleast partially reducing or inhibiting the activity of LTC4S; or atleast partially reducing or inhibiting the expression of LTC4S.

As used herein, the term “subject” refers to primates (e.g., humans,male or female), dogs, rabbits, guinea pigs, pigs, rats and mice. Incertain embodiments, the subject is a primate. In yet other embodiments,the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers to alleviating or ameliorating the disease ordisorder (i.e., slowing or arresting the development of the disease orat least one of the clinical symptoms thereof); or alleviating orameliorating at least one physical parameter or biomarker associatedwith the disease or disorder, including those which may not bediscernible to the patient.

As used herein, the term “prevent”, “preventing” or “prevention” of anydisease or disorder refers to the prophylactic treatment of the diseaseor disorder; or delaying the onset or progression of the disease ordisorder

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturateddouble bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible stereoisomers, rotamers,atropisomers, tautomers or mixtures thereof, for example, assubstantially pure geometric (cis or trans) stereoisomers,diastereomers, optical isomers (antipodes), racemates or mixturesthereof.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Methods of Synthesizing the Spiropiperidinyl Derivatives of theInvention.

Agents of the invention, for example compounds in accordance to thedefinition of formula (I) wherein X1 is CH₂ and R² is H, may be preparedby a reaction sequence of the reaction schemes 1 and 2 below:

wherein PG is a nitrogen protecting group (e.g., benzyl (Bn),carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC) and other well knownnitrogen protecting groups), and R¹ is as defined in formula I,embodiment 1, and wherein R is an carboxylic acid protecting group, forexample a C₁₋₆alkyl or benzyl.

In method A, an intermediate 9 is formed by reacting an N-protectedpiperidinone (1) with an appropriately substituted aniline (2), beingtypically commercially available, to form intermediate 3, which isreacted with a Grignard reagent (such as allyl magnesium bromide) toform the intermediate 4. A cross-metathesis reaction of 4 with anappropriate acrylate ester provides 5. Hydrogenation of 5 in thepresence of a suitable catalyst, such as palladium on carbon or Adamscatalyst, produces intermediate 6 which is followed by carboxylic aciddeprotection (7) and dehydrative cyclization using a suitable reagent,such as SOCl₂. The spirocyclic lactam (8) thus formed can be deprotectedto form intermediate 9.

Depending of the selection of protecting groups for the amino group ofthe piperidine and the carboxylic acid, the deprotection methods must beadapted according to well known methods (such as hydrogenation, acid orbasic deprotection methods). For example, methyl or ethyl esterprotection for the carboxylic acid may be removed by saponification, anda tert-butyloxycarbonyl (Boc) protecting group for the piperidinenitrogen may be removed by treatment with hydrochloric acid in asuitable solvent, such as dioxane or diethyl ether.

For certain anilines (2) an alternative route can be followed (Method B)wherein N-acylation of intermediate 4 with acroloyl chloride is followedby a ring-closing metathesis reaction using Grubb's II catalyst toprovide the unsaturated lactam 11. Intermediate 11 may be saturatedunder suitable conditions such as hydrogenation, or by conjugatereduction with in situ generated nickel boride. Deprotection of thepiperidine nitrogen under suitable conditions as described aboveprovides intermediate 9.

Intermediate 9 may conveniently be reacted with a number of substratesto form the compounds of the invention, such as for example compoundscarrying a heteroaromatic ring (Scheme 2).

wherein R¹ and R⁴ are as defined in Formula I, embodiment 1.

Compounds of Formula (I) wherein X1 is O and R² is H are preparedaccording to Schemes 3 and 4:

Dihydroxylation of intermediate 4 followed by oxidative cleavage of theresulting diol using sodium periodate provides the unstable aldehyde 13which is reduced to the alcohol 14 using sodium borohydride. Cyclizationto intermediate 16 is effected in two steps by use of the phosgeneequivalent carbonyl diimidazole (CDI) to form the imidazolyl carbamate15, followed by treatment with pyridine hydrochloride. Intermediate 17is obtained by deprotection of the piperidine nitrogen under appropriateconditions depending on the nature of the protecting group as describedfor intermediate 9 in Scheme 1.

Intermediate 17 may conveniently be reacted with a number of substratesto form the compounds of the invention, such as for example compoundscarrying a heteroaromatic ring (Scheme 4).

Compounds of Formula (I) wherein X¹ is CH₂ and R² is F can be preparedaccording to Scheme 5 and 6:

A copper catalyzed conjugate borylation of the unsaturated lactam 11provides the boronate ester 18. Oxidation of the boronate ester undersuitable conditions, such as with sodium perborate results in formationof the beta-hydroxy lactam, which followed by piperidine nitrogendeprotection as described above provides the intermediate 20.

Compounds of the invention of formula (I) may be conveniently formed byreaction of intermediate 20 with a number of substrates, such as forexample compounds carrying an heteroaromatic ring, followed bydeoxyfluorination with DAST or similar reagents (Scheme 6).

In an additional embodiment, there is provided a compound or saltthereof selected from the group consisting of:

wherein PG is a nitrogen protecting group (e.g. benzyl (Bn),carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC) and the like); and PG²is a carboxylic acid protecting group (for example a C₁₋₆alkyl orbenzyl; PG³ is carbobenzyloxy (Cbz) or tert-butoxycarbonyl (BOC); eachR^(1a) is halo, each R^(1b) is independently selected from F and Cl; vis 1-3, and R¹ is phenyl optionally substituted with one, two or threehalo substituents.

In yet another embodiment, there is provided a compound or salt thereofselected from the group consisting of:

wherein PG and PG are as defined above.

Compounds of this embodiment are useful in the preparation of compoundsof the invention, e.g., compounds of Formula (I) or any one of Formula(II) to (V).

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure material. Compounds of the invention and intermediatescan also be converted into each other according to methods generallyknown to those skilled in the art.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In a further embodiment, the composition comprisesat least two pharmaceutically acceptable carriers, such as thosedescribed herein. The pharmaceutical composition can be formulated forparticular routes of administration such as oral administration,parenteral administration (e.g. by injection, infusion, transdermal ortopical administration), and rectal administration. Topicaladministration may also pertain to inhalation or intranasal application.The pharmaceutical compositions of the present invention can be made upin a solid form (including, without limitation, capsules, tablets,pills, granules, powders or suppositories), or in a liquid form(including, without limitation, solutions, suspensions or emulsions).Tablets may be either film coated or enteric coated according to methodsknown in the art. Typically, the pharmaceutical compositions are tabletsor gelatin capsules comprising the active ingredient together with oneor more of:

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium orcalcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt,or effervescent mixtures; and

e) absorbents, colorants, flavors and sweeteners.

Method of Use of the Invention

The compounds of any one of formulae (I) to (V) in free form or inpharmaceutically acceptable salt form, exhibit valuable pharmacologicalproperties, e.g. LTC4S modulating properties, e.g. as indicated in vitrotests as provided in the next sections, and are therefore indicated fortherapy or for use as research chemicals, e.g. as tool compounds.

Compounds of the invention may be useful in the treatment of anindication selected from: respiratory diseases/disorders, inflammationand/or disease/disorders having an inflammatory component, for exampleallergic disorders, asthma, childhood wheezing, chronic obstructivepulmonary disease, aspirin exacerbated respiratory disease,bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease(e.g. sarcoidosis, pulmonary fibrosis, scleroderma lung disease, andusual interstitial in pneumonia), ear nose and throat diseases (e.g.sinusitis, rhinitis, nasal polyposis, rhinosinusitis, otitis media, andallergic eosinophilic esophagitis), eye diseases (e.g. conjunctivitisand giant papillary conjunctivitis), skin diseases (e.g. psoriasis,atopic dermatitis, eczema and chronic urticaria), rheumatic diseases(e.g. rheumatoid arthritis, arthrosis, psoriasis arthritis,osteoarthritis, systemic lupus erythematosus, systemic sclerosis),vasculitis (e.g. Henoch-Schonlein purpura, Loffler's syndrome andKawasaki disease), cardiovascular diseases (e.g. atherosclerosis,cerebrovascular diseases, acute ischemic heart attacks and post-heartattack treatment), gastrointestinal diseases (e.g. eosinophilic diseasesin the gastrointestinal system, inflammatory bowel disease, irritablebowel syndrome, colitis, celiaci and gastric haemorrhagia), urologicdiseases (e.g. glomerulonephritis, interstitial cystitis, nephritis,nephropathy, nephrotic syndrome, hepatorenal syndrome, andnephrotoxicity), diseases of the central nervous system (e.g. cerebralischemia, spinal cord injury, migraine, multiple sclerosis, andsleep-disordered breathing), endocrine diseases (e.g. autoimmunethyreoiditis, diabetes-related inflammation), urticaria, anaphylaxis,angioedema, oedema in Kwashiorkor, dysmenorrhoea, burn-induced oxidativeinjury, multiple trauma, pain (inflammatory and neuropathic), endotoxinshock, sepsis, bacterial infections (e.g. from Helicobacter pylori,Pseudomonas aerugiosa or Shigella dysenteriae), fungal infections (e.g.vulvovaginal candidasis), viral infections (e.g. hepatitis, meningitis,parainfluenza and respiratory syncytial virus), hypereosinofilicsyndrome, and malignancies (e.g. Hodgkin's lymphoma, leukemia (e.g.eosinophil leukemia and chronic myelogenous leukemia), mastocytos,polycytemi vera, and ovarian carcinoma).

Thus, as a further aspect, the present invention provides the use of acompound of formula (I) or any one of Formulae (II) to (V) in therapy.In a further embodiment, the therapy is selected from a disease whichmay be treated by inhibition on LTC4S. In another embodiment, thedisease is selected from the afore-mentioned list, suitably allergicdisorders, asthma, aspirin exacerbated respiratory disease (AERD), COPD,cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis),nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilicgastrointestinal diseases and inflammatory bowel disease, and moresuitably asthma, atopic dermatitis or chronic urticaria.

Thus, as a further aspect, the present invention provides a compound ofany one formulae (I) to (V) for use in therapy. In a further embodiment,the therapy is selected from a disease which may be treated byinhibition of LTC4S. In another embodiment, the disease is selected fromthe afore-mentioned list, suitably allergic disorders, asthma, aspirinexacerbated respiratory disease (AERD), COPD, cystic fibrosis,dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis,rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseasesand inflammatory bowel disease, and more suitably asthma, atopicdermatitis or chronic urticaria.

In another aspect, the invention provides a method of treating a diseasewhich is treated by inhibiting LTC4S comprising administration of atherapeutically effective amount of a compound of any one of formulae(I) to (V). In a further embodiment, the disease is selected from theafore-mentioned list, suitably allergic disorders, asthma, aspirinexacerbated respiratory disease (AERD), COPD, cystic fibrosis,dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis,rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseasesand inflammatory bowel disease, and more suitably asthma, atopicdermatitis or chronic urticaria.

Thus, as a further aspect, the present invention provides the use of acompound of any one of formulae (I) to (V) for the manufacture of amedicament. In a further embodiment, the medicament is for treatment ofa disease which may be treated by inhibition of LTC4S. In anotherembodiment, the disease is selected from the afore-mentioned list,suitably allergic disorders, asthma, aspirin exacerbated respiratorydisease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis(allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis,eosinophilic gastrointestinal diseases and inflammatory bowel disease,and more suitably asthma, atopic dermatitis or chronic urticaria.

In another embodiment of the present invention, there is provided9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-onefor use in the treatment of a disease selected from the afore-mentionedlist, suitably for the treatment of an allergic disorders, asthma,aspirin exacerbated respiratory disease (AERD), COPD, cystic fibrosis,dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis,rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseasesand inflammatory bowel disease, and more suitably asthma, atopicdermatitis or chronic urticaria.

In another embodiment of the present invention, there is provided(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-onefor use in the treatment of a disease selected from the afore-mentionedlist, suitably for the treatment of an allergic disorders, asthma,aspirin exacerbated respiratory disease (AERD), COPD, cystic fibrosis,dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis,rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseasesand inflammatory bowel disease, and more suitably asthma, atopicdermatitis or chronic urticaria.

In another embodiment of the present invention, there is provided(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-onefor use in the treatment of a disease selected from the afore-mentionedlist, suitably for the treatment of an allergic disorders, asthma,aspirin exacerbated respiratory disease (AERD), COPD, cystic fibrosis,dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis,rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseasesand inflammatory bowel disease, and more suitably for the treatment ofasthma, atopic dermatitis or chronic urticaria.

In another embodiment of the present invention, there is provided1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-onefor use in the treatment of a disease selected from the afore-mentionedlist, or for the treatment of an allergic disorders, asthma, aspirinexacerbated respiratory disease (AERD), COPD, cystic fibrosis,dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis,rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseasesand inflammatory bowel disease, and more suitably for the treatment ofasthma, atopic dermatitis or chronic urticaria.

In another embodiment of the present invention, there is provided9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-onefor use in the treatment of the disease is selected from theafore-mentioned list, suitably allergic disorders, asthma, aspirinexacerbated respiratory disease (AERD), COPD, cystic fibrosis,dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis,rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseasesand inflammatory bowel disease, and more suitably for the treatment ofasthma, atopic dermatitis or chronic urticaria.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

Combination Product and Combination Therapy of the Invention:

“Combination” refers to either a fixed combination in one dosage unitform, or a combined administration where a compound of the presentinvention and a combination partner (e.g. another drug as explainedbelow, also referred to as “therapeutic agent” or “co-agent”) may beadministered independently at the same time or separately within timeintervals, especially where these time intervals allow that thecombination partners show a cooperative, e.g. synergistic effect. Thesingle components may be packaged in a kit or separately. One or both ofthe components (e.g., powders or liquids) may be reconstituted ordiluted to a desired dose prior to administration. The terms“co-administration” or “combined administration” or the like as utilizedherein are meant to encompass administration of the selected combinationpartner to a single subject in need thereof (e.g. a patient), and areintended to include treatment regimens in which the agents are notnecessarily administered by the same route of administration or at thesame time. The term “pharmaceutical combination” as used herein means aproduct that results from the mixing or combining of more than onetherapeutic agent and includes both fixed and non-fixed combinations ofthe therapeutic agents. The term “fixed combination” means that thetherapeutic agents, e.g. a compound of the present invention and acombination partner, are both administered to a patient simultaneouslyin the form of a single entity or dosage. The term “non-fixedcombination” means that the therapeutic agents, e.g. a compound of thepresent invention and a combination partner, are both administered to apatient as separate entities either simultaneously, concurrently orsequentially with no specific time limits, wherein such administrationprovides therapeutically effective levels of the two compounds in thebody of the patient. The latter also applies to cocktail therapy, e.g.the administration of three or more therapeutic agent.

The term “pharmaceutical combination” as used herein refers to either afixed combination in one dosage unit form, or non-fixed combination or akit of parts for the combined administration where two or moretherapeutic agents may be administered independently at the same time orseparately within time intervals, especially where these time intervalsallow that the combination partners show a cooperative, e.g. synergisticeffect.

The term “combination therapy” refers to the administration of two ormore therapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure.

Such administration encompasses co-administration of these therapeuticagents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of active ingredients. Alternatively, suchadministration encompasses co-administration in multiple, or in separatecontainers (e.g., tablets, capsules, powders, and liquids) for eachactive ingredient. Powders and/or liquids may be reconstituted ordiluted to a desired dose prior to administration. In addition, suchadministration also encompasses use of each type of therapeutic agent ina sequential manner, either at approximately the same time or atdifferent times. In either case, the treatment regimen will providebeneficial effects of the drug combination in treating the conditions ordisorders described herein.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents. Atherapeutic agent is, for example, a chemical compound, peptide,antibody, antibody fragment or nucleic acid, which is therapeuticallyactive or enhances the therapeutic activity when administered to apatient in combination with a compound of the invention.

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease orcondition mediated by LTC4S. Products provided as a combined preparationinclude a composition comprising the compound of any one of formulae (I)to (V) and the other therapeutic agent(s) together in the samepharmaceutical composition, or the compound of any one of formulae (I)to (V) and the other therapeutic agent(s) in separate form, e.g. in theform of a kit.

In one embodiment, the invention provides a pharmaceutical combinationcomprising a compound of any one of formulae (I) to (V) and anothertherapeutic agent(s). Optionally, the pharmaceutical combination maycomprise a pharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of any one of formulae (I) to (V). In one embodiment, the kitcomprises means for separately retaining said compositions, such as acontainer, divided bottle, or divided foil packet. An example of such akit is a blister pack, as typically used for the packaging of tablets,capsules and the like.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound of any one offormulae (I) to (V) for treating a disease or condition mediated byLTC4S, wherein the medicament is prepared for administration withanother therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition mediatedby LTC4S wherein the medicament is administered with a compound of anyone of formulas (I) to (V).

The invention also provides a compound of any one of formulae (I) to (V)for use in a method of treating a disease or condition mediated byLTC4S, wherein the compound of formula (I), (II), (III), (IV) or (V) isprepared for administration with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition mediated by LTC4S, wherein the othertherapeutic agent is prepared for administration with a compound offormula (I), (II), (III), (IV) or (V). The invention also provides acompound of formula (I) for use in a method of treating a disease orcondition mediated by LTC4S, wherein the compound of formula (I), (II),(III), (IV), or (V) is administered with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition mediated by LTC4S, wherein the othertherapeutic agent is administered with a compound of formula (I), (II),(III), (IV) or (V).

The invention also provides the use of a compound of an one of formulae(I) to (V) for treating a disease or condition mediated by LTC4S,wherein the patient has previously (e.g. within 24 hours) been treatedwith another therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition mediatedby LTC4S, wherein the patient has previously (e.g. within 24 hours) beentreated with a compound of formula (I), (II), (III), (IV) or (V).

In one embodiment, the other therapeutic agent is a therapeutic agentuseful in the treatment of a respiratory disorder and/or a therapeuticagent that is useful in the treatment of inflammation and disorders withan inflammatory component (anti-inflammatory drugs).

In one embodiment, the other therapeutic agent useful in the combinationtherapy is selected from steroid; corticosteroids; glucocorticosteroids;non-steroidal glucocorticoid receptor agonists; leukotriene receptorantagonists (LTRAs) including LTB4 antagonists, LTD4 antagonists,Leukotriene A4 hydrolase (LTA4H) inhibitors, Cysteinyl-LeukotrieneReceptor antagonists (including Montelukast, Pranlukast, Zafirlukast); amodulator of prostaglandin pathway (e.g. CRTH2/DP2 receptor antagonist);Bruton's tyrosine Kinase inhibitors (BTK inhibitors); PDE4 inhibitors;antihistamines; histamine H4 receptor antagonist; H1 receptorantagonists; beta-adrenergic drugs such as beta (β)-2-adrenoceptoragonists; anticholinergic drugs or and anticholinergic or antimuscarinicagents (e.g. M2 and/or M3 antagonists); nonsteroidal anti-inflammatorydrugs (“NSAIDs”); analgesics; inhibitors of 5-lipoxygenase; inhibitorsof FLAP (5-lipoxygenase activting protein); COX-2 selective inhibitorsand statins.

Suitable steroids are in particular, glucocorticosteroids, such asbudesonide, beclamethasone dipropionate, fluticasone propionate,fluticasone furoate, ciclesonide or mometasone furoate; or non-steroidalglucocorticoid receptor agonists, such as velsecorat (AZD7594)

Suitable PDE4 inhibitors include for example roflumilast, aprelimast,crisaborole, lotamilast, ensifentrine (RPL554), and CHF 6001.

Suitable beta (β)-2-adrenoceptor agonists are for example albuterol(salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol,procaterol, and especially, formoterol and pharmaceutically acceptablesalts thereof, and compounds (in free or salt or solvate form) offormula (I) of WO 00/75114, which document is incorporated herein byreference, preferably compounds of the Examples thereof, especially acompound of formula

and pharmaceutically acceptable salts thereof, as well as compounds (infree or salt or solvate form) of formula (I) of WO 04/16601. Furtherβ-2-adrenoreceptor agonists include vilanterol, olodaterol andabediterol.

Suitable bronchodilatory drugs include anticholinergic or antimuscarinicagents, in particular, ipratropium bromide, oxitropium bromide,tiotropium salts, glycopyrromium bromide, umeclidinium bromide andaclidinium bromide,

Suitable antihistamine (H1 antagonist) drug substances includecetirizine hydrochloride, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride.

Suitable β₂-agonists for use in the present invention include, but arenot limited to, arformoterol, bambuterol, bitolterol, broxaterol,carbuterol, clenbuterol, dopexamine, fenoterol, formoterol,hexoprenaline, ibuterol, Isoetharine, isoprenaline, levosalbutamol,mabuterol, meluadrine, metaprotenerol, nolomirole, orciprenaline,pirbuterol, procaterol, reproterol, ritodrine, rimoterol, salbutamol,salmefamol, salmeterol, sibenadet, sotenerot, sulfonterol, terbutaline,tiaramide, tulobuterol, carmoterol, QAB-149 (also known as indacaterol),olodaterol, abediterol and vilanterol and I, and combinations thereof,each of which is optionally in the form of a racemate, enantiomer,diastereomer, or mixtures thereof, and also optionally in the form of apharmacologically-compatible acid addition salt.

Suitable corticosteroids and glucocorticoids for use in the presentinvention include, but are not limited to, prednisolone,methylprednisolone, dexamethasone, naflocort, deflazacort, halopredoneacetate, budesonide, beclomethasone dipropionate, hydrocortisone,triamcinolone acetonide, fluocinolone acetonide, fluocinonide,clocortolone pivalate, methylprednisolone aceponate, dexamethasonepalmitoate, tipredane, hydrocortisone aceponate, prednicarbate,alclometasone dipropionate, halometasone, methylprednisolonesuleptanate, mometasone furoate, rimexolone, prednisolone farnesylate,ciclesonide, deprodone propionate, fluticasone propionate, fluticasonefuroate, halobetasol propionate, loteprednol etabonate, betamethasonebutyrate propionate, flunisolide, prednisone, dexamethasone sodiumphosphate, triamcinolone, betamethasone 17-valerate, betamethasone,betamethasone dipropionate, hydrocortisone acetate, hydrocortisonesodium succinate, prednisolone sodium phosphate, hydrocortisoneprobutate and combinations thereof.

Suitable LTD4 antagonists for use in the present invention include, butare not limited to, tomelukast, ibudilast, pobilukast, pranlukasthydrate, zafirlukast, ritolukast, verlukast, sulukast, cinalukast,iralukast sodium, montelukast sodium,4-[4-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxobutyric acid,[[5-[[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]aceticacid,9-[(4-Acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-(IH-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one,5-[3-[2-(7-Chloroquinolin-2-yl)vinyl]phenyl]-8-(N,N-dimethylcarbamoyl)-4,6-dithiaoctanoicacid sodium salt;3-[1-[3-[2-(7-Chloroquinolin-2-yl)vinyl]phenyl]-1-[3-(dimethylamino)-3-oxopropylsulfanyl]methylsulfanyl]propionicacid sodium salt,6-(2-Cyclohexylethyl)-[I,3,4]thiadiazolo[3,2-a]-I,2,3-triazolo[4,5-d]pyrimidin-9(IH-one,4-[6-Acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid,(R)-3-Methoxy-4-[1-methyl-5-[N-(2-methyl-4,4,4-trifluorobutyl)carbamoyl]indol-3-ylmethyl]-N-(2-methylphenylsulfonyl)benzamide,(R)-3-[2-Methoxy-4-[N-(2-methylphenylsulfonyl)carbamoyl]benzyl]-1-methyl-N-(4,4,4-trifluoro-2-methylbutyl)indole-5-carboxamide,(+)-4(S)-(4-Carboxyphenylthio)-7-[4-(4-phenoxybutoxy)phenyl]-5(Z)-heptenoicacid, compounds International Application No. PCT/EP03/12581, andcombinations thereof.

Suitable NSAIDs for use in the present invention include, but are notlimited to, Aceclofenac, acemetacin, acetylsalicylic acid, alclofenac,alminoprofen, amfenac, Ampiroxicam, Antolmetinguacil, Anirolac,antrafenine, azapropazone, benorylate, Bermoprofen, bindarit, bromfenac,bucloxic acid, Bucolom, Bufexamac, Bumadizon, butibufen, Butixirat,Carbasalatcalcium, carprofen, choline magnesium trisalicylate,celecoxib, Cinmetacin, Cinnoxicam, clidanac Clobuzarit Deboxamet,dexibuprofen, Dexketoprofen, diclofenac, diflunisal, droxicam, Eltenac,Enfenaminsaure, Etersalat, etodolac, etofenamate, etoricoxib,Feclobuzon, felbinac, fenbufen, fenclofenac, fenoprofen, fentiazac,Fepradinol, Feprazon, Flobufen, floctafenine, flufenamic acid,flufenisal, Flunoxaprofen, flurbiprofen, Flurbiprofenaxetil, Furofenac,Furprofen, Glucametacin, ibufenac, ibuprofen, Indobufen, indomethacin,Indometacinfarnesil, indoprofen, Isoxepac, Isoxicam, ketoprofen,ketorolac, lobenzarit, Lonazolac, lornoxicam, Loxoprofen, lumiracoxib,meclofenamic, Meclofen, mefenamic acid, meloxicam, mesalazine, MiroProfen, Mofezolac, nabumetone, naproxen, niflumic acid, olsalazine,oxaprozin, Oxipinac, oxyphenbutazone, parecoxib, phenylbutazone,Pelubiprofen, Pimeprofen, Pirazolac, Priroxicam, pirprofen, Pranoprofen,Prifelon, Prinomod, Proglumetacin, Proquazon, Protizininsaure,rofecoxib, Romazarit, salicylamide, salicylic acid, Salmi Stein,Salnacedin, salsalate, sulindac, sudoxicam, suprofen, Talniflumate,tenidap, Tenosal, tenoxicam, tepoxalin, tiaprofenic acid, Taramid,Tilnoprofenarbamel, timegadine, Tinoridin, Tiopinac, tolfenamic acid,tolmetin, Ufenamat, valdecoxib, Ximoprofen, zaltoprofen, Zoliprofen andcombinations thereof.

Suitable Leukotriene A4 hydrolase inhibitors include compounds describedin WO 2015/092740, WO2014/164658, WO2014/152536, WO2014/152518,WO2014/152229, WO2012/125598, WO2013/012844, WO2014/014874,WO2013/134226, WO2015/009609, WO2015/009611, WO2013/131901.

Of particular interest is a compound described in WO 2015/092740; forexample a compound selected from(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; or pharmaceutically acceptable salt thereof).

Other LTA4H inhibitors of particular interest include Acebilustat,CTX-3397 or a compound disclosed in WO2014/164658 and more specificallycompound which is:4-(((1S,4S)-5-(4-(4-(oxazol-2-yl)phenoxy)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzoicacid:

or a pharmaceutically acceptable salt thereof.

Suitable histamine H4 receptor antagonist include for example a compounddescribed in U.S. Pat. No. 7,943,628; and preferably the compound ofexample 9 which isN⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine:

or a pharmaceutically acceptable salt thereof, preferably L-titrate saltthereof.

Suitable BTK inhibitors include for example Ibrutinib, Acalabrutinib(ACP-196), Evobrutinib; Fenebrutinib; Tirabrutinib (ONO-4059, GS-4059);Zanubrutinib (BGB-3111), Spebrutinib (CC-292, AVL-292), Poseltinib(HM-71224, LY3337641), Vecabrutinib (SNS-062) BMS-986142; BMS986195;PRN2246; PRN1008, M7583, CT1530, BIIBO68, AC-0058TA, ARQ-531, TAK-020,TG1701 or a compound described in WO2015/079417, WO2015/083008,WO2015/110923, WO2014/173289, WO2012/021444, WO2013/081016,WO2013/067274, WO2012/170976, WO2011/162515, US2017/119766,WO2016/065226, U.S. Pat. No. 9,688,676, WO2016/201280, WO2017/059702,U.S. Pat. No. 9,630,968, US2014/0256734, WO2017118277, WO2014/039899,WO/16/105531, WO2018/005849, WO2013/185082 or in Journal of MedicinalChemistry, 2016 59 (19) 9173-9200.

Of particular interest, BTK inhibitors include compound of example 31described in WO2014/039899, compound of the following structure:

described as compound 14f in Journal of Medicinal Chemistry, 2016, 59(19), 9173-9200; compound of example 2 described in US2017/119766,compound of example 223 described in WO2016/065226 which is:

or compound 1 described in WO2016/201280, compound 1 described inWO2017/059702, or compound 1 described in WO2017/118277; or apharmaceutically acceptable salt thereof.

Of other particular interest, BTK inhibitors include a compounddescribed in WO2015/079417, for example a compound selected fromN-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof.

Suitable CRTH2/DP2 receptor antagonists include Fevipiprant, Timapiprantor[8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]aceticacid L-lysine salt (GB001) or a pharmaceutically acceptable saltthereof.

In a prefered embodiment, the second therapeutic agent is selected from:

1. a modulator of prostaglandin pathway (e.g. CRTH2/DP2 receptorantagonist, for example Fevipiprant);

2. a Leukotriene A4 hydrolase inhibitor (more specifically, a compounddescrived in WO 2015/092740; preferably a compound selected from(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; or pharmaceutically acceptable salt thereof);

3. a histamine H4 receptor antagonist (for example a compound describedin U.S. Pat. No. 7,943,628; and preferably the compound of example 9which isN⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine:

or a pharmaceutically acceptable salt thereof, preferably L-titrate saltthereof; and

4. a BTK inhibitor (for example a compound described in WO2015/079417,and preferably a compound selected fromN-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, there is provided a productcomprising1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-oneor a pharmaceutically salt thereof, and a second therapeutic agentselected from Fevipiprant,(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid;N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof as a combined preparationfor simultaneous, separate or sequential use in therapy.

In one embodiment of the invention, there is provided a productcomprising9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-oneor a pharmaceutically salt thereof, and a second therapeutic agentselected from Fevipiprant,(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid;N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof as a combined preparationfor simultaneous, separate or sequential use in therapy.

In one embodiment of the invention, there is provided a productcomprising1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-oneor a pharmaceutically salt thereof and a second therapeutic agentselected from Fevipiprant,(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid;N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof as a combined preparationfor simultaneous, separate or sequential use in therapy.

In one embodiment of the invention, there is provided a productcomprising9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-oneor a pharmaceutically salt thereof and a second therapeutic agentselected from Fevipiprant,(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid;N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof as a combined preparationfor simultaneous, separate or sequential use in therapy.

In one embodiment of the invention, there is provided a productcomprising(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one,or(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;or a pharmaceutically acceptable salt thereof, and a second therapeuticagent selected from Fevipiprant,(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid;N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof as a combined preparationfor simultaneous, separate or sequential use in therapy.

In one embodiment of the invention, there is provided a pharmaceuticalcomposition comprising9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one,or a pharmaceutically salt thereof; a second therapeutic agent selectedfrom Fevipiprant,(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid;N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In one embodiment of the invention, there is provided a pharmaceuticalcomposition comprising9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one,or a pharmaceutically salt thereof; a second therapeutic agent selectedfrom Fevipiprant,(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid;N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In one embodiment of the invention, there is provided a pharmaceuticalcomposition comprising(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one,or(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one,or a pharmaceutically salt thereof; a second therapeutic agent selectedfrom Fevipiprant,(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid;N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In one embodiment of the invention, there is provided a pharmaceuticalcomposition comprising9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one,or a pharmaceutically salt thereof; a second therapeutic agent selectedfrom Fevipiprant,(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid;N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In one embodiment of the invention, there is provided a pharmaceuticalcomposition comprising1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one,or a pharmaceutically salt thereof; a second therapeutic agent selectedfrom Fevipiprant,(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid;(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid;N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-Acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-Amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)—N-(3-(6-Amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamideandN-(3-(6-Amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

Biological Assays and Data

The activity of a compound according to the present invention can beassessed by the following in vitro methods. A compound of formula (I) ora pharmaceutically acceptable salt thereof, exhibit valuablepharmacological properties, e.g. properties susceptible to LTC4S, e.g.,as indicated in tests as provided in the next sections and are thereforeindicated for therapy related to LTC4S.

A. Human LTC4S Enzymatic Assay:

LTC₄ synthase catalyzes the conversion of Leukotriene A₄ (LTA₄) toLeukotriene C4 (LTC₄) in the presence of reduced glutathione (GSH) as aco-substrate. For compound testing, compounds are delivered as 10 mMstock solutions in 90% DMSO in matrix tubes. From this, a 1:3 dilutiondose response series is prepared with a starting concentration of 30 μMto 0.1 nM. For the enzymatic assay 97.5 nL of compound/DMSO solution istransferred to each well and 5 μL enzyme solution (assay buffer: 50 mMbis-tris propane pH 7.3, 250 mM NaCl, 10 mM MgCl₂, 0.001% MGN3) is addedto the wells. The final enzyme concentration in the assay is 0.75 nM.The enzyme compound mixture is incubated at room temperature for 15minutes prior to the addition of 5 μL substrate solution. As the primarysubstrate LTA₄ is a highly unstable intermediate of the arachidonic acidpathway, LTA₄ is substituted for a more stable LTA₄ methyl ester form(LTA₄-Me) for the purposes of screening. A final substrate concentrationof 400 μM GSH and 5 μM LTA₄-Me is chosen.

The LTA₄-Me is obtained commercially in 2% triethylamine/hexane solvent.As this solvent is incompatible with the HTRF assay it has to beexchanged with DMSO according to following procedure: add 50 μL of 100%DMSO to 50 μL LTA₄-Me (3 mM) in a 2 mL Eppendorf tube and mix gently byinverting the tube. The triethylamine/hexane is evaporated under aconstant argon flux at room temperature. The DMSO-LTA₄-Me (3 mM) isaliquoted and stored at −20° C. for not longer than 4 weeks, as it isnot stable in DMSO due to its oxidizing properties.

Upon addition of the substrate, the plate is immediately placed on ashaker for 5 min at room temperature. Immediately after the 5 minincubation 5 μL of H₂O₂ solution is added to all wells to stop thereaction. The plate contents are mixed before the addition of detectionreagents. The conversion from LTA₄-Me and GSH to LTC₄-Me is quantifiedusing a LTC₄-Me standard curve ranging from 1.5 μM to 0.08 nM. For thedetection of the product of the enzymatic reaction LTC₄-Me, the CisbioLTC₄-HTRF kit is used as the assay is compatible with the detection ofLTC₄-Me. 5 μL of diluted LTC₄-d2 conjugate (according to manufacturer'sprotocol) are added to all wells of the assay plate and the contentsgently mixed and incubated for 5 minutes at room temperature. Then 5 μLof the diluted LTC₄-Eu3+ cryptate (according to manufacturer's protocol)are added to all wells and the contents of the plate gently mixed andincubated 60 min at room temperature before reading the plate on theSpectramax Paradigm (Molecular Devices) using ratiometric analysis(665/616 nM) and the following setup: number of flashes/well of 30,integration time of 0.3 ms, excitation time of 0.05 ms, positioningdelay of 0.03 ms, and a ratio multiplicator of 10000. The percentinhibition for each point of an inhibition curve is calculated afterdata interpolation using the LTC₄-Me standard curve, to convert the HTRFsignal to the amount of LTC₄-Me produced within the LTC₄S catalyzedreaction on each plate. The data is analyzed using parametric curvefitting to determine IC₅₀ values of LTC₄S inhibitors. Due to the assaysetup, the maximally detectable potency of compounds is at around 2-4nM. Therefore compounds with a potency that may theoretically result inIC₅₀ values lower than 2 nM are measured from diluted stock solutions,usually with 1 μM starting concentration in the assay.

B. Human Whole Blood HTRF Assay

LTC₄ synthase catalyzes the conversion of Leukotriene A₄ (LTA₄) toLeukotriene C4 (LTC₄) in the presence of reduced glutathione (GSH) as aco-substrate. For testing the inhibition of LTC₄S, compounds areprepared for either eight-point or sixteen-point dose response studiesin 384-well Labcyte low dead volume (LDV) plates. For eight-point doseresponse studies, compounds are diluted 1:5 starting at 1 μMconcentration in 90% DMSO. For sixteen-point dose response studies,compounds are diluted 1:3.333 starting at 10 μM concentration in 90%DMSO. Compounds are studied in duplicates. Ten wells are filled with 90%DMSO which correspond to the stimulated and unstimulated control wells.On the day before the assay is run, 100 nL from each well, i.e., eachcompound at each concentration, are printed from the Labcyte LDV plateinto each corresponding well on the assay plate (Greiner BioOne #784201)using a Labcyte Echo 650 acoustic liquid handler and stored at 4° C. Themorning of the assay, whole blood is collected from three human donors.Donors must be non-smokers and must not have taken NSAIDs within the 48hours prior to blood collection. The amount of blood collected per donordepends on the amount of compounds to be tested and the dose responseformat in which they are to be studied (about 8 mL of whole blood foreither 22 compounds in 8-point dose response format or 11 compounds in16-point dose response format). Whole blood from the three donors isdiluted 1:3 in RPMI 1640 medium (Gibco #72400-047). 50 μL of dilutedblood are then dispensed into each assay plate well with pre-dispensedcompounds and DMSO for the stimulated and unstimulated controls using aThermo Scientific™ Multidrop™ Combi reagent dispenser, and incubated at37° C. for 4 hours. Calcium ionophore A23187 is used to induce a rapidincrease in intracellular levels of Ca²⁺. The Ca²⁺ functions as auniversal second messenger in various immune cells, such as T cells, Bcells and mast cells, and is used to induce degranulation and release ofeicosanoids, including LTC₄, by cells contained in the whole bloodsamples. Shortly before the completion of the 4-hour incubation, 0.5mg/mL calcium ionophore A23187 is prepared by mixing (for 1 mL) 20 μL of25 mg/mL calcium ionophore A23187 stock solution (Sigma-Aldrich #C-7522)in 950 μL of warmed-up (37° C.) RPMI 1640 medium and 30 μL of dimethylsulfoxide (DMSO). All but the unstimulated control wells aresubsequently stimulated by dispensing 1 μL of the 0.5 mg/mL calciumionophore suspension using the Thermo Scientific™ Multidrop™ Combireagent dispenser. Plates are incubated for 15 minutes at 37° C. Platesare then centrifuged at 300 g for 10 minutes at room temperature topellet blood cells and stop the reaction. Finally, 25 μL of theresulting supernatants are collected from each well using a BeckmanCoulter Biomek FXP automated liquid handler into empty 384-well plates(Greiner BioOne #781281) for storage. Plates are sealed and stored at−80° C.

In order to measure the amount of LTC₄ released by cells in the humanblood samples during calcium ionophore stimulation, supernatants areanalyzed using the Cisbio LTC₄ homogeneous time-resolved FRET (HTRF) kit(Cisbio #64LC4PEH). Supernatants from human whole blood are thawed anddiluted by transferring 3.5 μL from each well into high-base, low-volumewhite plates (Greiner BioOne #784075) already containing 6.5 μL ofDiluent #3 solution (Cisbio #62DL3DDD). Ten serially diluted standardcurve solutions are also dispensed in duplicate into each plate asinstructed in the protocol. Blank controls and cryptate control wellsare also prepared. Then, 5 μL of anti-LTC₄-d2 working solution aredispensed into all the wells, but the cryptate control wells.Subsequently, 5 μL of anti-LTC₄-Eu3+ cryptate working solution aredispensed into all the wells. Plates are then covered with a lid andincubated at room temperature for one hour with gentle orbital shaking(˜450 rpm). Time resolved fluorescence at 665 and 620 nm is measuredafter the incubation using a BMG LABTECH CLARIOstar® (50 flashes perwell, integration starting at 60 μs for 400 μs, 12.0 mm focal height).HTRF ratios are calculated for each well by dividing the 665 nmintensity by the 620 nm intensity, and multiplying the resulting ratioby 10,000. LTC₄ standard curves are interpolated for each plate and usedto convert the HTRF ratio readouts into the amount of LTC₄ present ineach well (in ng/mL). Parametric curve fitting is used to obtaininhibition curves and IC₅₀ values.

TABLE 1 human LTC4S IC₅₀ human whole blood Example# (enzymatic assay)HTRF IC₅₀  1 6 13  2 36 —  3 8 180  4 7 50  5 5 10  6a 190 310  6b 44 — 7 76 100  8 7 —  9 2 48 10 — 5 11 — 6 12 — 2 13 — 36 14 — 1  15a — 1 15b — 180 16 — 16 17 — 9 18 — 2 19 — 3 20 12 64 21 4 7 22 11 530 23 6145 24 33 110 25 62 170 26 16 110 27 25 59 28 110 450 29 57 180 30 13 36031 15 120 32 7 170 33 24 56 34 — 2  35a 12 40  35b 3 — 36 6 44 37 12 12038 8 86 39 — 4 40 — 4 41 — 5 42 — 410 43 — 400 44 13 — 45 — 620 46 — 49047 — 7 48 — 45 49 — 88 50 — 45 51 — 70 52 — 29 53 — 1140 54 — 300 55 — 656 — 17 57 — 850 58 — 560 59 — 640 60 — 680 61 — 29 62 — 410 63 — 430 64— 2 65 — 1 66 — 1  67, racemic — 2 68 — 120 69 — 35 70 — 110 71 — 580 72— 760 73 — 68 74 — 4 75 — 4 76 — 57 77 — 31 78 — 24 79 — 56 80 — 24 8113 72 82 12 21 83 9 9 84 8 9 85 — 430  86, racemic — 2 87 — 7 88 — 1370 89a — 1  89b — 5 90 — 4 91 — 3 92 — 5 93 — 10 94 — 830  95, racemic — 2 96, racemic — 3 97 — 3 98 — 3 99 — 4 100  — 2 101  — 5 102, racemic — 9103  — 8 104, racemic — 5 105, racemic — 6 106  — 69 107  — 6 108,racemic — 22 109  — 15 110a — 3 110b — 5 111, racemic — 17 112  — 67113a — 15 113b — 36 114  — 7 115  — 28 116a — 13 116b — 33 117  — 18118  — 8 119  — 29 120  — 32

EXEMPLIFICATION OF THE INVENTION

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Compounds of the present disclosure may be prepared by methods known inthe art of organic synthesis. In all of the methods it is understoodthat protecting groups for sensitive or reactive groups may be employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1999) ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons). Thesegroups are removed at a convenient stage of the compound synthesis usingmethods that are readily apparent to those skilled in the art.

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectraare given in ppm (δ) and coupling constants, J, are reported in Hertz.Tetramethylsilane (TMS) was used as an internal standard. Chemicalshifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50),methanol (δ 3.31), chloroform (δ 7.26) or other solvent as indicated inNMR spectral data. A small amount of the dry sample (2-5 mg) isdissolved in an appropriate deuterated solvent (1 mL). The chemicalnames were generated using ChemBioDraw Ultra v12 from CambridgeSoft.

Temperatures are given in degrees Celsius. If not mentioned otherwise,all evaporations are performed under reduced pressure, typically betweenabout 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of finalproducts, intermediates and starting materials is confirmed by standardanalytical methods, e.g., microanalysis and spectroscopiccharacteristics, e.g., MS, IR, NMR. Abbreviations used are thoseconventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art.

Abbreviations Used in the Following Examples and Elsewhere Herein are:

2-MeTHF 2-methyltetrahydrofuran

ACN acetonitrile

AcOH acetic acid

Bn or Bzl benzyl

Boc tert-butyloxycarbonyl

Boc₂O di-tert butyl dicarbonate

B₂Pin₂ 4,4,4,4,5,5,5,5-Octamethyl-2,2-bi-1,3,2-dioxaborolane,bis(pinacolato)diboron

br broad

brine saturated aqueous NaCl solution

cHex cyclohexane

d doublet

DAST (diethylamino)sulfur trifluoride

DBU 1,8-diazabicyclo(5.4.0)undec-7-ene

DCE dichloroethane

DCM dichloromethane

dd doublet of doublets

DIAD diisopropyl azodicarboxylate

DIBAH diisobutylaluminium hydride

DIPEA diisopropylethylamine

DMAP dimethylaminopyridine

DME 1,2-dimethoxyethane

DMF N,N-dimethyl formamide

DMSO dimethylsulfoxide

DPEPhos bis[(2-diphenylphosphino)phenyl] ether

EDC.HCl N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride

Et₂O diethylether

EtOAc ethyl acetate

EtOH ethanol

eq equivalent(s)

equiv. equivalent(s)

Ex example(s)

h hour

HCl hydrochloric acid

HOBt 1-hydroxybenzotriazol

HPLC high performance liquid chromatography

IPA iso-propanol

LC liquid chromatography

LiHMDS lithium bis(trimethylsilyl)amide

m multiplet/milli, depending on the context

mCPBA 3-chloroperoxybenzoic acid

MeCN acetonitrile

MeOH methanol

mg milligram

min minutes

MS mass spectrometry

mL milliliter

mmol millimol

MTBE methyl tert-butyl ether

m/z mass to charge ratio

NMR nuclear magnetic resonance

ppm parts per million

PyBrop bromo-tris-pyrrolidino-phosphonium hexafluorophosphate

q quartet

quint quintet

RT room temperature

RP reversed phase

s singlet

SFC supercritical fluid chromatography

t triplet

TBME tert-butylmethylether

tBu tert-butyl

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMSCN trimethylsilylcyanide

t_(R) retention time

UPLC ultra performance liquid chromatography

Analytical Details

NMR: Measurements were performed on a Bruker Ultrashield™ 400 (400 MHz),Bruker Ultrashield™ 600 (600 MHz), Agilent VNMRS-300 (300 MHz),spectrometer using or not trimethylsilane as an internal standard.Chemical shifts (δ-values) are reported in ppm downfield fromtetramethylsilane, spectra splitting pattern are designated as singlet(s), doublet (d), triplet (t), quartet (q), quintet (quint), multiplet,unresolved or overlapping signals (m), broad signal (br). Deuteratedsolvents are given in parentheses.

LC-MS:

LCMS Method a:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity HSS T3, 2.1×50 mm, 1.8 μm; column temperature: 60° C.

Gradient: from 5 to 98% B in 1.4 min, A=water+0.05% formic acid+3.75 mMammonium acetate, B=acetonitrile+0.04% formic acid, flow: 1.0 mL/min.

LCMS Method b:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity CSH C18, 2.1×50 mm, 1.7 μm; column temperature: 50° C.

Gradient: from 5 to 98% B in 1.8 min, A=water+0.1% NH₃,B=acetonitrile+0.1% NH₃, flow: 1.0 mL/min.

LCMS Method c:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity BEH C18, 2.1×50 mm; column temperature: 50° C.

Gradient: from 3 to 98% B in 4.8 min, A=water+0.05% formic acid,B=acetonitrile+0.05% formic acid, flow: 0.6 mL/min.

LCMS Method d:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity BEH C18, 2.1×50 mm, 1.7 μm; column temperature: 40° C.

Gradient: from 3 to 98% B in 2.8 min, A=water+0.1% formic acid,B=acetonitrile+0.1% formic acid, flow: 0.8 mL/min.

LCMS Method e:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity BEH C18, 2.1×30 mm, 1.7 μm; column temperature: 40° C.

Gradient: from 3 to 98% B in 2.8 min, A=water+0.1% formic acid,B=acetonitrile+0.1% formic acid, flow: 1 mL/min.

LCMS Method f:

System: Agilent LC/MSD

Column: Zorbax C18, 4.6×150 mm, 5 μm; column temperature: 40° C.

Gradient: 30% to 70% B in 1 min, 70 to 100% B in 5 min; A=water+0.1%TFA, B=acetonitrile; flow: 1.0 mL/min.

LCMS Method q:

System: Agilent LC/MSD

Column: Kinetex C18 4.6×100 mm, 5 μm; column temperature: 40° C.

Gradient: 0-20% B in 2 min, 20-70% B in 8 min, 70-100% B in 3 min;A=water, B=acetonitrile; flow: 0.75 mL/min.

LCMS Method h:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity BEH C18, 2.1×30 mm, 1.7 μm; column temperature: 40° C.

Gradient: from 2 to 98% B in 1.5 min, A=water+5 mM ammonium hydroxide,B=acetonitrile+5 mM ammonium hydroxide, flow: 1.0 mL/min.

LCMS Method i:

System: Waters Acquity UPLC with Waters SQ detector

Column: Acquity BEH C18, 2.1×30 mm, 1.7 μm

Mobile phases, gradient: A=water+0.05% formic acid, B=methanol+0.04%formic acid; time (min)/% of B: 0.0/2, 0.10/2, 0.50/80, 0.60/95,0.80/95, 0.90/2, 1.15/2

Flow rate: 1.0 mL/min

LCMS Method:

System: Shimadzu LCMS 2020

Column: Synergi max-RP 100 Å Mercury, 4.0×30 mm, 2.5 μm; columntemperature: 40° C.

Mobile phases, gradient: A=0.1% HCOOH in water, B=acetonitrile; time(min)/% of B: 0/5, 0.1/5, 0.5/5, 1.0/95, 1.5/95, 2.0/5, 3.0/5

Flow rate: 2.0 mL/min

Detection: PDA, 210 nm

LCMS Method k:

System: Agilent LC/MSD

Column: Kinetex EVO, 4.6×50 mm, 2.6 μm; column temperature: 40° C.

Mobile phases, gradient: A=0.1% HCOOH in water, B=acetonitrile; time(min)/% of B: 0.0/20, 0.25/20, 01.0/95.0, 2.5/95, 3.0/20, 4/20

Flow rate: 1.5 mL/min

Detection: PDA, 210 nm

LCMS Method l:

System: Sciex API-2000

Column: Synergi max-RP 100 Å Mercury, 4.0×30 mm, 2.5 μm; columntemperature: 30° C.

Mobile phases, gradient: A=0.1% HCOOH in water, B=acetonitrile; time(min)/% of B: 0/30, 0.5/30, 1.5/95, 2.4/95, 2.5/30, 3.0/30

Flow rate: 2.0 mL/min

Detection: TWC PDA

LCMS Method m:

System: Agilent 1200-6120

Column: Poroshell 120 EC-C18, 4.6×50 mm, 2.7 μm; column temperature: 40°C.

Mobile phases, gradient: A=0.1% formic acid in water, B=0.1% formic acidin acetonitrile; time (min)/% of B: 0/5, 4.0/95, 6.0/95

Flow rate: 1.2 mL/min

Detection: PDA, 210 nm

Preparative Methods:

Flash Chromatography System:

System: Teledyne ISCO, CombiFlash Rf.

Column: pre-packed RediSep Rf cartridges.

SFC:

System: Waters Preparative SFC-100-MS system:

Detection: Waters 2998 Photodiode Array Detector

-   -   Waters MS Single Quadrupole Detection

Modifier: Methanol

ABPR: 120 bar

Column temperature: 40° C.

Flow rate: 100 g/min.

Prep HPLC (RP):

System: Waters Autopurification-MS System

Detection: Waters 2998 Photodiode Array Detector

-   -   Waters MS Single Quadrupole Detection

Column temperature: RT

Eluent A: water

Eluent B: acetonitrile, both containing 0.1% TFA or 0.1% NH₄OH

All reagents, starting materials and intermediates utilized in theseexamples were available from commercial sources or were readily preparedby methods known to those skilled in the art.

Intermediate A: 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

Step A: tert-butyl4-cyano-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate)

TMSCN (20.2 ml, 151 mmol) was added to solution of tert-butyl4-oxopiperidine-1-carboxylate (15 g, 75 mmol) and 3,4-difluoroaniline(7.5 mL, 75 mmol) in 10 ml of AcOH. The reaction mixture was stirred at100° C. for 3 h, partioned between water and DCM and extracted threetimes. The combined organic extracts were dried over Na₂SO₄, filtered,and concentrated. The residue was trituated with diethylether and theproduct was filtered off as a beige solid (19.25 g, 55.9 mmol). ¹H NMR(400 MHz, DMSO-d₆) δ=7.27 (dd, 1H), 6.84 (ddd, 1H), 6.69 (m, 1H), 6.29(s, 1H), 3.78 (m, 2H), 3.16 (m, 2H), 2.27 (m, 2H), 1.74 (m, 2H), 1.44(s, 9H) ppm; m/z=382.3 [M+HCO₂]⁻; t_(R)=1.13 min (LCMS method a).

Step B: tert-butyl4-allyl-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate

Allyl magnesium bromide (1.0 M in diethyl ether, 86 mL, 86 mmol) wasadded dropwise under argon atmosphere to a stirred solution oftert-butyl4-cyano-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate) (19.3 g,57.1 mmol) in 300 mL of THF cooled to 0° C. The reaction mixture wasallowed to reach RT and stirred for 16 h. The mixture was acidified with2 M aqueous HCl, diluted with DCM, washed with water and brine. Theaqueous layers were extracted twice with DCM. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. Purificationby silica gel chromatography (0-40% MeOH in EtOAc) provided tert-butyl4-allyl-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate (7.38 g,20.5 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.07 (dt, 1H), 6.71 (m, 1H),6.54 (dt, 1H), 5.7 (m, 1H), 5.34 (s, 1H), 5.01 (m, 2H), 3.59 (m, 2H),3.09 (m, 2H), 2.43 (m, 2H), 1.87 (m, 2H), 1.42 (m, 2H), 1.40 (s, 9H)ppm; m/z=353.2 [M+H]⁺; t_(R)=1.32 min (LCMS method a).

Step C: tert-butyl(E)-4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobut-2-en-1-yl)piperidine-1-carboxylate

Ethyl acrylate (2.5 ml, 23.0 mmol) and Hoveyda-Grubbs Catalyst 2ndGeneration (656 mg, 1.05 mmol) were added under argon to a solution oftert-butyl 4-allyl-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate (7.38 g, 20.9 mmol) in 200 mL of toluene.The reaction mixture was stirred for 16 h at 110° C., cooled to RT,absorbed on Isolute and evaporated to dryness. Purification by silicagel chromatography (0-45% EtOAc in cyclohexane) provided tert-butyl(E)-4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobut-2-en-1-yl)piperidine-1-carboxylate(5.00 g, 11.2 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.09 (dd, 1H), 6.76 (m,2H), 6.56 (m, 1H), 5.86 (d, 1H), 5.50 (s, 1H), 4.07 (q, 2H), 3.59 (m,2H), 3.08 (m, 2H), 2.64 (d, 2H), 1.88 (m, 2H), 1.48 (m, 2H), 1.40 (s,9H), 1.20 (t, 3H) ppm; m/z=425.3 [M+H]⁺; t_(R)=1.28 min (83%, trans),1.30 min (14%, cis) (LCMS method a).

Step D: tert-butyl4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobutyl)piperidine-1-carboxylate

PtO₂ (1.34 g, 0.589 mmol) was added under an argon atmosphere to asolution of tert-butyl(E)-4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobut-2-en-1-yl)piperidine-1-carboxylate(5.0 g, 11.78 mmol) in 75 mL of MeOH. The reaction mixture was evacuatedand ventilated three times with H₂. The reaction mixture was thenstirred for another 1 h at RT. Additional PtO₂ (1.337 g, 0.589 mmol) wasadded and the reaction mixture stirred for another hour at 40° C. Thenthe reaction mixture was flushed with argon and filtered over Hyflo®filter aid. The filtrate was absorbed on Isolute® and evaporated todryness. Purification by silica gel chromatography (0-40% EtOAc incyclohexane) provided tert-butyl4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobutyl)piperidine-1-carboxylate(4.42 g, 9.84 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.06 (dd, 1H), 6.66 (m,1H), 6.49 (m, 1H), 5.34 (s, 1H), 4.07 and 4.00 (q, 2H), 3.57 (m, 2H),3.06 (m, 2H), 2.21 (t, 2H), 1.89 (m, 2H), 1.64 (m, 2H), 1.4-1.5 (m, 4H),1.40 (s, 9H), 1.20 and 1.15 (t, 3H) ppm; m/z=427.4 [M+H]⁺; t_(R)=1.29min (UPLC-MS method a).

Step E:4-(1-(tert-butoxycarbonyl)-4-((3,4-difluorophenyl)amino)piperidin-4-yl)butanoicAcid

LiOH (496 mg, 20.71 mmol) was added to a solution of tert-butyl4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobutyl)piperidine-1-carboxylate (4.42 g, 10.35mmol) in 40 mL of THF/water (1:1) and the reaction mixture stirred for16 h at 55° C. The reaction mixture was acidified with citric acid anddiluted with DCM. The aqueous layer was extracted three times with DCM.The combined organic extracts were dried with Na₂SO₄, filtered, andconcentrated. The resulting solid was dried under vacuum. The crude4-(1-(tert-butoxycarbonyl)-4-((3,4-difluorophenyl)amino)piperidin-4-yl)butanoicacid (3.81 g, 9.08 mmol) was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ=11.89 (br s, 1H), 7.06 (m,1H), 6.67 (m, 1H), 6.50 (m, 1H), 5.33 (s, 1H), 3.58 (m, 2H), 3.07 (m,2H), 2.13 (t, 2H), 1.89 (m, 2H), 1.77 (m, 2H), 1.63 (m, 2H), 1.41 (m,2H), 1.40 (s, 9H) ppm; m/z=399.4 [M+H]⁺; t_(R)=1.13 min (LCMS method a).

Step F: tert-butyl1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-carboxylate

To a solution of4-(1-(tert-butoxycarbonyl)-4-((3,4-difluorophenyl)amino)piperidin-4-yl)butanoicacid (3.81 g, 9.56 mmol) in 100 mL of dry EtOAc was added SOCl₂ (2.4 mL,33.5 mmol) and the reaction mixture stirred for 2 h at RT. The reactionmixture was treated with water and extracted three times with ethylacetate. The combined organic layers were dried over Na₂SO₄, filteredand concentrated. Purification by reverse phase column chromatography(RP C18, 10-100% MeOH in water) provided tert-butyl1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-carboxylate(3.64 g, 9.57 mmol); m/z=381.2 [M+H]⁺; t_(R)=1.00 min (LCMS method a).

Step G: 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

To a solution of tert-butyl1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate(3.64 g, 9.57 mmol) in dioxane (25 mL) was added HCl (4 M in dioxane, 25mL). The reaction mixture was stirred for 2 h at RT. The solid wascollected by filtration and washed with dioxane. The HCl salt wassolubilized in water and DCM. The pH was adjusted to ˜10 by addition of2 M Na₂CO₃ solution. The aqueous layer was back extracted three timewith DCM. The combined organic extracts were dried over Na₂CO₃,filtered, and concentrated to provide1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (3.00 g, 9.00mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.46 (dd, 1H), 7.20 (m, 1H), 6.90 (m,1H), 2.74 (m, 2H), 2.62 (m, 2H), 2.38 (t, 2H), 2.03 (m, 2H), 1.62-1.81(m, 4H), 1.46 (m, 2H) ppm, NH not observed; m/z=281.2 [M+H]⁺; t_(R)=0.49min (LCMS method a).

Intermediate B:1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: tert-butyl4-((4-chloro-3-fluorophenyl)amino)-4-cyanopiperidine-1-carboxylate)

TMSCN (5.97 g, 60.2 mmol) was added to a solution of tert-butyl4-oxopiperidine-1-carboxylate (10 g, 50 mmol) and4-chloro-3-fluoroaniline (8.77 g, 60.2 mmol) in 100 mL of acetic acid.The resulting reaction mixture was stirred for 23 h at RT. Then themixture was cooled to 0° C. and concentrated ammonium hydroxide solutionwas added until a pH of 12 was reached. The precipitate was washed withwater and dried under vacuum to provide tert-butyl4-((4-chloro-3-fluorophenyl)amino)-4-cyanopiperidine-1-carboxylate)(16.23 g, 45.0 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.35 (dd, 1H), 6.80(d, 1H), 6.71 (d, 1H), 6.61 (s, 1H), 3.77 (m, 2H), 3.18 (m, 2H), 2.31(m, 2H), 1.77 (m, 2H), 1.41 (s, 9H) ppm; m/z=398.3 [M+H]⁺; t_(R)=1.22min (LCMS method a).

Step B: tert-butyl4-allyl-4-((4-chloro-3-fluorophenyl)amino)piperidine-1-carboxylate

Tert-butyl4-((4-chloro-3-fluorophenyl)amino)-4-cyanopiperidine-1-carboxylate) (12g, 33.9 mmol) was dissolved in 125 mL of dry THF and cooled to 0° C.under argon. Allymagnesium bromide (1.0 M solution in diethylether, 51mL, 51 mmol) was added dropwise at 0° C. The reaction mixture wasstirred for 2 h at 0° C., then allowed to warm to RT. The reactionmixture was quenched with saturated aqueous NH₄Cl and extracted threetimes with ethyl acetate. The organic extracts were dried over Na₂SO₄,filtered, and concentrated. Purification by silica gel chromatography(0-10% EtOAc in cyclohexane) provided tert-butyl4-allyl-4-((4-chloro-3-fluorophenyl)amino)piperidine-1-carboxylate (7.76g, 19.8 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.15 (dd, 1H), 6.69 (d, 1H),6.60 (d, 1H), 5.67 (s, 1H), 5.63-5.73 (m, 1H), 4.97-5.04 (m, 2H), 4.01(m, 1H), 3.59 (m, 2H), 3.30 (m, 1H), 2.46 (m, 2H), 1.88-1.91 (m, 2H),1.43-1.50 (m, 2H), 1.39 (s, 9H) ppm; m/z=369.4 [M+H]⁺; t_(R)=1.4 min(LCMS method a).

Step C: tert-butyl4-allyl-4-(N-(4-chloro-3-fluorophenyl)acrylamido)piperidine-1-carboxylate

A solution of tert-butyl4-allyl-4-((4-chloro-3-fluorophenyl)amino)piperidine-1-carboxylate (8.54g, 23.2 mmol) and acryloyl chloride (5.6 mL, 70 mmol) in 200 mL oftoluene was heated to reflux for 1 h. Triethylamine (16.1 mL, 116 mmol)was added and the mixture was refluxed for 4 h. After cooling to RT, themixture was diluted with water and extracted twice with DCM. The organicextracts were dried over Na₂SO₄, filtered, and concentrated.Purification by silica gel chromatography (0-60% EtOAc in cyclohexane)provided tert-butyl4-allyl-4-(N-(4-chloro-3-fluorophenyl)acrylamido)piperidine-1-carboxylate(5.86 g, 13.6 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.67 (t, 1H), 7.38 (dd,1H), 7.17-7.07 (m, 1H), 6.05 (dd, 1H), 6.02-5.84 (m, 1H), 5.67 (dd, 1H),5.42 (dd, 1H), 5.26-5.07 (m, 2H), 3.66 (d, 2H), 3.31 (s, 3H), 3.05 (t,1H), 2.09 (s, 2H), 1.98 (s, 1H), 1.49-1.36 (m, 1H), 1.36 (s, 9H) ppm;m/z=423.4 [M+H]⁺; t_(R)=1.36 min (LCMS method a).

Step D: tert-butyl1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate

Grubbs II catalyst (0.859 g, 1.37 mmol) was added to a solution oftert-butyl4-allyl-4-(N-(4-chloro-3-fluorophenyl)acrylamido)piperidine-1-carboxylate(5.8 g, 14 mmol) in 20 mL of toluene under argon. The solution washeated to 110° C. and stirred for 4 h. The reaction mixture was cooledto RT, adsorbed onto silica gel, and evaporated to dryness. Purificationby silica gel chromatography (0-100% EtOAc in cyclohexane) providedtert-butyl1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate(2.90 g, 6.98 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.64 (dd, 1H), 7.33 (d,1H), 7.06 (d, 1H), 6.73 (d, 1H), 5.98 (d, 1H), 2.8-3.3 (m, 4H), 1.86 (m,2H), 1.33 (s, 9H), 1.40-1.16 (m, 4H) ppm; m/z=395.4 [M+H]⁺; t_(R)=1.09min (LCMS method a).

Step E: tert-butyl1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate

tert-Butyl1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate(2.9 g, 7.34 mmol) was dissolved in 25 mL of MeOH and cooled to 0° C.NiCl₂.6H₂O (0.476 g, 3.67 mmol) was added and the resulting reactionmixture was stirred for 10 min. NaBH₄ (0.556 g, 14.7 mmol) was addedslowly and the mixture was stirred 0° C. for 2 hr. The reaction mixturewas evaporated under reduced pressure. The crude product was dissolvedin ethyl acetate, washed with brine and dried over Na₂SO₄. Removal ofsolvent under reduced pressure yielded the crude tert-butyl1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate(2.54 g, 6.27 mmol) which was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ=7.62 (dd, 1H), 7.23 (d, 1H),6.96 (d, 1H), 3.76 (m, 2H), 2.87 (m, 2H), 2.41 (t, 2H), 2.04 (m, 2H),1.79 (m, 4H), 1.42 (m, 2H), 1.30 (s, 9H) ppm; m/z=397.4 [M+H]⁺;t_(R)=1.08 min (LCMS method a).

Step F: 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

Trifluoroacetic acid (3.88 mL, 50.4 mmol) was added under argon to asolution of tert-butyl1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate(2.00 g, 5.04 mmol) in DCM (20 mL) cooled to 0° C. The reaction mixturewas allowed to warm up to RT and stir for 2 h. The reaction mixture wasquenched with saturated aqueous NaHCO₃ and was extracted three timeswith DCM. The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated. The resulting solid was triturated withdiethyl ether, isolated by filtration, and dried under vacuum to provide1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one (1.32 g,4.36 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=8.59 (br, 1H), 7.98 (br, 1H),7.67 (dd, 1H), 7.29 (dd, 1H), 6.99 (dd, 1H), 2.95-3.20 (m, 4H), 2.40 (t,2H), 2.07 (m, 2H), 1.93 (m, 2H), 1.74-1.83 (m, 4H) ppm; m/z=297.3[M+H]⁺; t_(R)=0.39 min (LCMS method a).

Intermediate C: Synthesis of1-(4-chlorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

The title compound was synthesized analogously to Intermediate Bstarting with 4-chloroaniline. ¹H NMR (600 MHz, DMSO-d₆) δ=8.5 (br, 1H),7.89 (br, 1H), 7.51 (d, 2H), 7.11 (d, 2H), 3.13 (m, 2H), 3.00 (m, 2H),2.41-2.37 (m, 2H), 2.11-2.05 (m, 2H), 1.95-1.88 (m, 2H), 1.83-1.76 (m,2H), 1.72 (m, 2H) ppm; m/z=279.2 [M+H]⁺; t_(R)=0.38 min (LCMS method a).

Intermediate D:1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one

Step A: tert-butyl4-allyl-4-(N-(3,4-difluorophenyl)acrylamido)piperidine-1-carboxylate

DIEA (193 g, 1490 mmol) was added to a solution of tert-butyl4-allyl-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate (105 g,298 mmol) in DCM (1.0 L) cooled to 0° C. under an atmosphere ofnitrogen. The mixture was stirred at 25° C. for 1 h. Acryloyl chloride(135 g, 1490 mmol) was added to the solution and the reaction wasstirred at 25° C. for 11 h. The reaction was poured into water (1.0 L),then the mixture was extracted with DCM (500 mL×3). The combined organiclayers were washed with brine (1.0 L), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Silica gel chromatography (10:1petroleum ether:EtOAc) provided tert-butyl4-allyl-4-(N-(3,4-difluorophenyl)acrylamido)piperidine-1-carboxylate(80.1 g, 197 mmol) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ=7.55-7.44 (m, 1H), 7.44-7.35 (m, 1H), 7.13-7.03 (m, 1H), 6.09-5.99 (m,1H), 5.98-5.84 (m, 1H), 5.71-5.59 (m, 1H), 5.44-5.34 (m, 1H), 5.24-5.16(m, 1H), 5.15-5.06 (m, 1H), 3.80-3.53 (m, 2H), 3.14-2.80 (m, 4H),2.18-1.87 (m, 2H), 1.52-1.37 (m, 2H), 1.37-1.31 (m, 9H).

Step B: tert-butyl1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate

To a solution of tert-butyl4-allyl-4-(N-(3,4-difluorophenyl)acrylamido)piperidine-1-carboxylate (50g, 123 mmol) in toluene (500 mL) was added Grubbs-II (7.70 g, 12.3 mmol)at 25° C. The mixture was stirred at 120° C. for 12 hrs under N₂. Thesolution was cooled to RT, concentrated under reduced pressure, and theresidue purified by silica chromatography (15-100% EtOAc in petroleumether) to provide tert-butyl1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate(35 g, 93 mmol) as grey solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.52-7.41 (m,1H), 7.39-7.29 (m, 1H), 7.07-6.96 (m, 1H), 6.76-6.64 (m, 1H), 6.02-5.90(m, 1H), 3.90-3.65 (m, 2H), 3.01-2.79 (m, 2H), 2.78-2.73 (m, 2H),1.90-1.79 (m, 2H), 1.39-1.25 (m, 11H); m/z=379.1 [M+H]⁺

Step C: tert-butyl1-(3,4-difluorophenyl)-2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,9-diazaspiro[5.5]undecane-9-carboxylate

B₂Pin (7.4 g, 29 mmol) in THF (50 mL) was added dropwise to a stirredsolution of CuCl (130 mg, 1.32 mmol), NaOt-Bu (7.60 g, 79.2 mmol) andDPEPhos (7.12 g, 13.2 mmol) in THF (50 mL), under an atmosphere ofnitrogen.1-(3,4-Difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate(10 g, 26.4 mmol) in MeOH (30 mL) followed by THF (20 mL) was added. Thereaction mixture was heated at 80° C. for 12 h. LCMS analysis indicatedcomplete conversion of the starting material to the pinacol boronateester (m/z=507.2 [M+H]⁺). The reaction was filtered, and the filtratewas directly used in the next step.

Step D: tert-butyl1-(3,4-difluorophenyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate

To a solution of NaBO₃.4H₂O (11.7 g, 52.8 mmol) in H₂O (120 mL) wasadded the THF solution of tert-butyl1-(3,4-difluorophenyl)-2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,9-diazaspiro[5.5]undecane-9-carboxylatefrom Step C. The reaction mixture was then heated at 25° C. for 12 h.The mixture was poured into water (100 mL), and extracted with DCM(3×100 mL). The combined organic extracts were washed with brine (200mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purification by silica gel chromatography (DMC/MeOH=1:0 to10:1) provided tert-butyl1-(3,4-difluorophenyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate(6.0 g, 15 mmol) as white solid.

Step E:1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one

HCl in dioxane (4.0 M, 50 mL) was added to a stirred solution oftert-butyl1-(3,4-difluorophenyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate(10.0 g, 25.2 mmol) in dioxane (50 mL). The reaction mixture was thenheated at 25° C. for 6 h. The reaction was concentrated under reducedpressure and the residue was slurried in MTBE (100 mL) at 25° C. for 1h. The solids were isolated by filtration providing1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one,hydrochloride salt (8.0 g, 24 mmol), as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ=9.13-8.81 (m, 1H), 8.41-8.11 (m, 1H), 7.62-7.42 (m, 1H),7.37-7.20 (m, 1H), 7.04-6.83 (m, 1H), 4.13-4.06 (m, 1H), 3.22-3.09 (m,2H), 3.07-2.90 (m, 2H), 2.76-2.63 (m, 1H), 2.49-2.45 (m, 1H), 2.38-2.26(m, 1H), 2.01-1.65 (m, 5H); m/z=297.1 [M+H]⁺

Intermediate E:1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one

Step A: tert-butyl4-((3,4-difluorophenyl)amino)-4-(2,3-dihydroxypropyl)piperidine-1-carboxylate

A solution of N-methylmorpholine N-oxide (8.043 g, 68.75 mmol) in water(20 mL) was added to a stirred solution of tert-butyl4-allyl-4-((3,4-difluorophenyl) amino) piperidine-1-carboxylate (11 g,31 mmol) in THF (35 mL) at −7° C. under an atmosphere of argon. Asolution of OsO₄ (1.56 mmol) in t-BuOH (24 mL) was added dropwise to thereaction mixture at −9° C. The mixture was then allowed to stir at −9°C. for 12 hours after which time sodium bisulphite solution was added toquench the reaction. The solution was extracted with EtOAc, the organiclayer was washed with brine solution, dried over Na₂SO₄, filtered, andconcentrated to a brown sticky solid (12.2 g, 31.6 mmol). This crudematerial was taken for the next step without purification. m/z=387.15[M+H]⁺

Step B: tert-butyl4-((3,4-difluorophenyl)amino)-4-(2-oxoethyl)piperidine-1-carboxylate

A solution of NaIO₄ (2.64 g, 12.4 mmol) in water (20 mL) was added to astirred solution of tert-butyl4-((3,4-difluorophenyl)amino)-4-(2,3-dihydroxypropyl)piperidine-1-carboxylate(4.0 g, 10 mmol) in MeOH (20 mL). The reaction mixture was stirred at RTfor 2 h under an argon atmosphere. The mixture was diluted with water,extracted with EtOAc, washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to provide the crude product as abrown sticky solid (3.17 g, 8.94 mmol). The crude was taken directly tothe next step without further purification.

Step C: tert-butyl4-((3,4-difluorophenyl)amino)-4-(2-hydroxyethyl)piperidine-1-carboxylate

Sodium borohydride (0.20 g, 5.4 mmol) was added to a stirred solution oftert-butyl4-((3,4-difluorophenyl)amino)-4-(2-oxoethyl)piperidine-1-carboxylate(1.6 g, 4.5 mmol) in MeOH (10 mL) at 0° C. The reaction mixture wasstirred at RT for 12 h under an argon atmosphere. The reaction mixturewas diluted with water, extracted with EtOAc, washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure toprovide the crude tert-butyl4-((3,4-difluorophenyl)amino)-4-(2-hydroxyethyl)piperidine-1-carboxylateas brown sticky mass (1.14 g, 3.20 mmol). The crude product was takenfor the next step without further purification. m/z=357.15 [M+H]⁺

Step D: tert-butyl4-(2-((1H-imidazole-1-carbonyl)oxy)ethyl)-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate

1,1′-Carbonyldiimidazole (1.04 g, 6.40 mmol) was added to a stirredsolution of tert-butyl4-((3,4-difluorophenyl)amino)-4-(2-hydroxyethyl)piperidine-1-carboxylate(1.14 g, 3.20 mmol) in DCM (10 mL) at RT. The reaction mixture wasstirred at RT for 12 h under an argon atmosphere. The reaction wasdiluted with water, extracted with DCM, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide the crude tert-butyl4-(2-((1H-imidazole-1-carbonyl)oxy)ethyl)-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylateas a brown sticky solid (1.31 g, 2.91 mmol). The crude product was takendirectly to the next step without purification. m/z=451.20 [M+H]⁺

Step E: tert-butyl1-(3,4-difluorophenyl)-2-oxo-3-oxa-1,9-diazaspiro[5.5]undecane-9-carboxylate

Pyridine hydrochloride (1.00 g, 8.65 mmol) was added to a stirredsolution of tert-butyl4-(2-((1H-imidazole-1-carbonyl)oxy)-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate(1.29 g, 2.88 mmol) in MeCN (10 mL) at RT. The reaction mixture wasstirred at RT for 24 h under an argon atmosphere. The mixture wasdiluted with water, extracted with EtOAc, washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure to provide thecrude of tert-butyl1-(3,4-difluorophenyl)-2-oxo-3-oxa-1,9-diazaspiro[5.5]undecane-9-carboxylateas sticky brown solid (1.07 g, 2.80 mmol). The crude was taken for thenext step without further purification. m/z=383.1 [M+H]⁺

Step F: 1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecane-2-one

HCl in dioxane (4.0 M, 6.0 mL) was added to tert-butyl1-(3,4-difluorophenyl)-2-oxo-3-oxa-1,9-diazaspiro[5.5]undecane-9-carboxylate(0.600 g, 1.57 mmol) at 0° C. The reaction mixture was stirred at RT for2 hours under an argon atmosphere. The mixture was concentrated underreduced pressure. The solid was isolated by filtration, washing withdiethyl ether to provide the title compound (hydrochloride salt) as apale brown solid (0.350 g, 1.24 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ 8.83(s, 1H), 8.16 (s, 1H), 7.54 (dt, J=10.9, 9.0 Hz, 1H), 7.46 (ddd, J=11.6,7.4, 2.5 Hz, 1H), 7.11 (ddt, J=8.4, 3.9, 2.0 Hz, 1H), 4.44-4.26 (m, 2H),3.17 (d, J=13.2 Hz, 2H), 3.08-2.91 (m, 2H), 2.31 (t, J=5.5 Hz, 2H),2.09-1.94 (m, 2H), 1.77 (td, J=13.8, 4.5 Hz, 2H); m/z=283.1 [M+H]⁺;t_(R)=1.32 min (LCMS method m)

Example 1:1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: (E)-amino(2-(4-fluorophenyl)hydrazono)methanesulfonic Acid

A mixture of 2-(4-fluorophenyl)1-hydrazinecarbothiomide (2.5 g, 14mmol), Na₂MoO₄.2H₂O (163 mg, 0.675 mmol) and NaCl (316 mg, 5.40 mmol) in7 mL of water was cooled to 0° C. A 30% solution of hydrogen peroxide(6.9 mL, 68 mmol) was added dropwise to the cooled suspension. Duringthe addition of the first half, the temperature was kept below 7° C.Then the reaction became exothermic and the temperature reached 76° C.while being cooled with ice bath. Once the addition was completed, thesuspension was stirred under ice bath cooling for 1.5 h. The suspensionwas filtered and the solid was washed with 10-15 mL cold brine to afforda beige solid (1.76 g) which was used in the next step without furtherpurification. m/z=493.3 [M+H]⁺; t_(R)=0.38 min (LCMS method a).

Step B:1-(4-chloro-3-fluorophenyl)-N′-(4-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboximidhydrazide

A mixture of1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate B, 1.95 g, 6.58 mmol),(E)-amino(2-(4-fluorophenyl)hydrazono)-methanesulfonic acid (1.76 g,7.56 mmol) and pyridine (1.17 mL, 14.5 mmol) in 9 mL of acetonitrile wasstirred for 1 h at 120° C. under microwave irradiation. The reactionmixture was concentrated and used in the next step without furtherpurification. m/z=448.2 [M+H]⁺; t_(R)=0.67 min (LCMS method a).

Step C:1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

1-(4-chloro-3-fluorophenyl)-N′-(4-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboximidhydrazide(2.95 g, 6.58 mmol) and trimethyl orthoformate (1.5 mL, 6.58 mmol) wereheated for 24 h at 90° C. under microwave irradiation. The reactionmixture was filtered through a short silica pad, eluted by 20% MeOH inDCM and evaporated. Purification by silica gel chromatography (0-10%MeOH in DCM) provided the title compound (140 mg, 0.291 mmol). ¹H NMR(400 MHz, DMSO-d₆) δ=8.85 (s, 1H), 7.74 (m, 2H), 7.60 (dd, 1H), 7.34(dd, 2H), 7.24 (dd, 1H), 6.98 (d, 1H), 3.85-3.88 (m, 2H), 2.99 (t, 2H),2.42 (m, 2H), 2.09 (m, 2H) 1.85-1.88 (m, 4H), 1.64 (td, 2H) ppm.m/z=458.1 [M+H]⁺; t_(R)=1.06 min (LCMS method a).

Example 2:1-(4-chloro-3-fluorophenyl)-9-(6-(trifluoromethyl)benzo[d]oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate B, 80 mg, 0.27 mmol),2-chloro-6-(trifluoromethyl)benzo[d]oxazole (60 mg, 0.27 mmol) andtriethylamine (0.11 mL, 0.81 mmol) were dissolved in 1.5 mL of EtOH andstirred for 30 min at 160° C. under microwave irradiation. The reactionmixture was concentrated and purification by silica gel chromatography(0-20% MeOH in EtOAc) provided the title compound (49 mg, 0.097 mmol).¹H NMR (400 MHz, DMSO-d₆) δ=7.73 (d, 1H), 7.59 (dd, 1H), 7.49 (dd, 1H),7.36 (d, 1H), 7.24 (dd, 1H), 6.96 (dd, 1H), 4.04 (m, 2H), 3.36 (m, 2H)2.45 (m, 2H), 2.15 (m, 2H), 1.95 (br d, 2H), 1.82-1.91 (m, 2H), 1.66 (m,2H) ppm; m/z=482.2 [M+H]⁺; t_(R)=1.22 min (LCMS method a).

By employing similar methods as described for the preparation of Example2, using appropriate commercially available chloroheterocycles andIntermediate B, the following compounds were prepared:

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 3

443.2; 1.19 min, LCMS method a ¹H NMR (400 MHz, DMSO-d₆) δ = 8.59 (d,1H), 7.56 (t, 1H), 7.20 (d, 1H), 6.93 (m, 2H), 4.50 (m, 2H), 3.07 (t,2H), 2.45 (t, 2H), 2.16 (m, 2H), 1.86-1.93 (m, 4H), 1.49-1.56 (dt, 2H)ppm. 4

493.3; 1.31 min, LCMS method a ¹H NMR (400 MHz, DMSO-d₆) δ = 9.22 (s,1H), 7.97 (d, 1H), 7.65 (s, 1H), 7.53 (dd, 1H), 7.41 (dd, 1H), 7.22 (dd,1H), 6.95 (d, 1H), 4.74 (m, 2H), 3.12 (t, 2H), 2.46 (t, 2H), 2.2 (m,2H), 1.89-1.99 (m, 4H), 1.56 (m, 2H) ppm.

Example 5:1-(4-chloro-3-fluorophenyl)-9-(2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one

1,3-dimethyluracil (1.855 g, 13.24 mmol) and sodium ethoxide (21%solution in EtOH, 13.6 mL, 36.4 mmol) were added to a solution of3-(trifluoromethyl)-1H-pyrazol-5-amine (1.00 g, 6.62 mmol) in 30 mL ofEtOH. The reaction mixture was stirred for 12 h at 60° C. The mixturewas concentrated, diluted with ethyl acetate and washed with 1 M HCl (40mL) and brine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated. Purification by silica gel chromatography (20-80% EtOAc incyclohexane, then 0-20% MeOH in EtOAc) provided2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (188 mg, 0.463mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=12.47 (br s, 1H), 8.59 (d, J=8 Hz,1H), 6.33-6.11 (m, 2H) ppm; m/z=202.1 [M−H]⁻, t_(R)=0.65 min (LCMSmethod a).

Step B: 5-chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

A mixture of POCl₃ (5.0 mL, 54 mmol) and2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (188 mg, 0.463mmol) was stirred for 1 h at 80° C. The mixture was cooled to RT andconcentrated. Purification by silica gel chromatography (0-50% EtOAc incyclohexane) provided5-chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (98 mg, 0.44mmol). ¹H NMR (600 MHz, DMSO-d₆) δ=9.34 (dd, 1H), 7.43 (d, 1H), 7.31 (s,1H) ppm; t_(R)=1.03 min (LCMS method a).

Step C:1-(4-chloro-3-fluorophenyl)-9-(2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

5-chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (95 mg, 0.43 mmol)and TEA (0.16 mL, 1.1 mmol) were added to a solution of1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate B, 85 mg, 0.29 mmol) in 4 mL of EtOH. The reaction mixturewas heated for 2 h at 15000 under microwave irradiation, evaporated,diluted with EtOAc and washed with saturated aqueous NaHCO₃ and brine.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification by SFC (Princeton 4-ethylpyridine, 30×250, 5μm; 15-25% MeOH in CO₂, 10 min) provided the title compound (122 mg,0.248 mmol). ¹H NMR (600 MHz, DMSO-d₆) δ=8.69 (dd, 1H), 7.58 (dd, 1H),7.24 (dd, 1H), 6.96 (dd, 1H), 6.89 (d, 1H), 6.40 (s, 1H), 4.31 (m, 2H),3.09 (t, 2H), 2.43 (t, 2H), 2.15 (m, 2H), 1.92 (m, 2H), 1.86 (m, 2H),1.55 (m, 2H) ppm; m/z=482.3 [M+H]⁺; t_(R)=1.14 min (LCMS method a).

Example 6a:1-(4-chloro-3-fluorophenyl)-9-(5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one,or1-(4-chloro-3-fluorophenyl)-9-(5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

and

Example 6b:1-(4-chloro-3-fluorophenyl)-9-(5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one,or1-(4-chloro-3-fluorophenyl)-9-(5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A:1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carbonitrile

Cyanogen bromide (3.0 M in DCM, 1.12 mL, 3.37 mmol) was added dropwiseto a solution of1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate B, 1.00 g, 3.37 mmol) and DIPEA (0.589 mL, 3.37 mmol) in35 mL of DCM. The reaction mixture was stirred for 1 h at RT. Brine wasadded to the reaction mixture. The organic layer was separated, driedover Na₂SO₄, filtered, and concentrated. The crude product was used inthe next step without further purification. m/z=322.2 [M+H]⁺; t_(R)=0.77min (LCMS method a).

Step B:1-(4-chloro-3-fluorophenyl)-N-hydroxy-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboximidamide

Hydroxylamine (50% in water, 0.89 mL, 15 mmol) was added to a solutionof1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carbonitrile(1.17 g, 3.64 mmol) in 30 mL of EtOH. The reaction mixture was stirredfor 1 h at 80° C., concentrated and was used in the next step withoutpurification. m/z=355.3 [M+H]⁺; t_(R)=0.47 min (LCMS method a).

Step C:1-(4-chloro-3-fluorophenyl)-9-(5-((1R,2R/1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

HOBt (926 mg, 6.05 mmol), EDC.HCl (1160 mg, 6.05 mmol) and DIPEA (1.2mL, 7.00 mmol) were added to a solution of racemic(1R,2R)-2-(trifluoromethyl)cyclopropanecarboxylic acid (754 mg, 4.65mmol) in DMF (30 mL). The reaction mixture was stirred for 10 min at RT.1-(4-chloro-3-fluorophenyl)-N-hydroxy-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboximidamide(1.23 g, 2.67 mmol) was added and the mixture was stirred for 72 h atRT. The mixture was concentrated, diluted with TBME and washed twicetimes with water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The crude product was purified by silica gelchromatography (0-6% MeOH in EtOAc) to providerac-1-(4-chloro-3-fluorophenyl)-9-(5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one(794 mg). ¹H NMR (400 MHz, DMSO-d₆) δ=7.61 (dd, 1H), 7.23 (dd, 1H), 6.96(m, 1H), 3.64 (m, 2H), 3.05 (m, 2H), 2.70 (m, 1H), 2.59 (m, 1H), 2.4 (t,2H), 2.08 (m, 2H), 1.87-1.78 (m, 4H), 1.58-1.46 (m, 4H) ppm; m/z 473.3[M+H]]⁺; t_(R)=1.14 min (LCMS method a). Preparative chiral HPLC(Chiralpak AD-H, 5 μm, 20×250 mm; mobile phase heptane:EtOH:MeOH70:15:15; flow rate 15 mL/min; 60 min elution) provided Example 6a (peak1, 304 mg, t_(R)=40.6 min) and Example 6b (peak 2, 303 mg, t_(R)=50.0min).

Example 7:1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

This compound was synthesized analogously to Examples 6a and 6b using3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid. ¹H NMR (600MHz, DMSO-d₆) δ=7.61 (dd, 1H), 7.23 (dd, 1H), 6.96 (dd, 1H), 3.65 (m,2H), 3.07 (dd, 2H), 2.41 (m, 8H), 2.08 (m, 2H), 1.86-1.81 (m, 4H),1.57-1.53 (m, 2H) ppm; m/z=499.2 [M+H]⁺; t_(R)=1.24 min (LCMS method a).

Example 8:1-(4-chloro-3-fluorophenyl)-9-(6-hydroxy-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A:9-(6-chloro-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate B, 100 mg, 0.337 mmol) in DMF (0.5 mL) was added dropwiseto a solution of trichloro-1,2,4-triazine (93 mg, 0.505 mmol) and TEA(0.094 mL, 0.674 mmol) in DMF (0.5 mL) and cooled to 0° C. The ice bathwas taken away and the reaction mixture allowed to reach RT and stirrfor 20 min. Pyrrolidine (0.28 mL, 3.4 mmol) was added and the reactionmixture stirred for 20 min at RT. The reaction mixture was diluted withEtOAc and washed with water. The organic layer was separated and theremaining aqueous layer was extracted twice with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated.Purification by silica gel chromatography (10-100% EtOAc in cyclohexane)provided9-(6-chloro-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(98 mg, 0.20 mmol) as a yellow powder. ¹H NMR (400 MHz, DMSO-d₆) δ=7.61(dd, 1H), 7.23 (d, 1H), 6.96 (d, 1H), 4.21 (m, 2H), 3.3-3.5 (m, 4H),3.12 (t, 2H), 2.43 (t, 2H), 2.13 (m, 2H), 1.8-1.95 (m, 8H), 1.7 (m, 2H)ppm; m/z=479.2 [M+H]⁺; t_(R)=0.96 min (LCMS method a).

Step B:1-(4-chloro-3-fluorophenyl)-9-(6-hydroxy-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

9-(6-chloro-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(78 mg, 0.163 mmol) was dissolved in a mixture of 2 mL of aceticacid/0.1 mL of water and heated under microwave irradiation for 11 h at120° C. After evaporation, the residue was dissolved in DCM and treatedwith triethylamine. The resulting mixture was evaporated and purified bySFC (Reprospher PEI 100 Å, 5 μm, 30×250 mm; 14-18% MeOH in CO₂, 10 min).¹H NMR (400 MHz, DMSO-d₆) δ=11.7 (s, 1H), 7.60 (t, 1H), 7.23 (d, 1H),6.96 (d, 1H), 5.7 (br, 1H), 4.6 (br, 1H), 3.18 (m, 4H), 3.1 (br, 2H),2.43 (m, 2H), 2.15 (m, 2H), 1.75-1.95 (m, 8H), 1.6 (m, 2H) ppm;m/z=461.2 [M+H]⁺; t_(R)=0.90 min (LCMS method a).

Example 9:1-(4-chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A:9-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 3,5-dibromo-1-methylpyrazin-2(1H)-one (1 g, 3.73 mmol),1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate B, 1.11 g, 0.373 mmol) and K₂CO₃ (1.55 g, 11.2 mmol) inDMF (11 mL) here heated under microwave irradiation for 1 h at 160° C.The reaction mixture was filtered and concentrated. Purification bysilica gel chromatography (0-10% MeOH in DCM) provided9-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(770 mg, 1.51 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.61 (dd, 1H), 7.27 (s,1H), 7.23 (dd, 1H), 6.97 (m, 1H), 4.55 (m, 2H), 3.28 (s, 3H), 2.94 (t,2H), 2.42 (t, 2H), 2.11 (m, 2H), 1.64-1.83 (m, 4H), 1.6-1.63 (m, 2H)ppm; m/z=483.0, 485.0 [M+H]⁺; t_(R)=1.02 min (LCMS method a).

Step B:1-(4-chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of9-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(150 mg, 0.31 mmol), (4-fluorophenyl)boronic acid (45 mg, 0.31 mmol),K₃PO₄ (132 mg, 0.62 mmol) and PdCl₂(dtbpf) (20 mg, 0.031 mmol) in 3:1dioxane/water (2.7 mL) was heated for 20 min at 90° C. Then the reactionmixture was cooled, diluted with water and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification by silica gel chromatography (0-5% MeOH inDCM) provided1-(4-chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one(34 mg, 0.065 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.76-7.78 (m, 2H), 7.72(s, 1H), 7.59 (t, 1H), 7.18-7.26 (m, 3H), 6.98 (m, 1H), 4.58 (m, 2H),3.4 (s, 3H), 2.95 (t, 2H), 2.44 (t, 2H), 2.15 (m, 2H), 1.86 (m, 4H),1.66-1.73 (m, 2H) ppm; m/z=499.1 [M+H]⁺; t_(R)=1.13 min (LCMS method a).

Example 10:9-(2-benzyl-3-oxo-6-(2-azaspiro[3.3]heptan-2-yl)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A:9-(6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate A, 0.673 g, 2.41 mmol),4-bromo-6-chloropyridazin-3(2H)-one (0.500 g, 2.41 mmol) and DIPEA (1.3mL, 7.2 mmol) in DMF (8 mL) were heated at 100° C. for 12 hours. Aftercooling to RT, water was added and the mixture extracted with EtOAc,washed with brine and dried over Na₂SO₄. After filtration, concentrationunder reduced pressure provided the crude9-(6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-oneas pale yellow gummy solid (1.355 g) which was taken on withoutpurification. m/z=272 [M+H]⁺

Step B:9-(2-benzyl-6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

Sodium hydride (0.070 g, 2.94 mmol) and benzyl bromide (0.249 g, 1.47mmol) were added to a stirred solution of9-(6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(0.400 g, 0.980 mmol) in THF (8 mL) cooled to 0° C. The reaction mixturewas allowed to warm to RT over five hours. Water was added to thereaction mixture and it was extracted with EtOAc. The extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. Purification by silica gel chromatography (60-70%EtOAc:hexane) provided9-(2-benzyl-6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-oneas a gummy white solid (1.355 g, 2.716 mmol). m/z=499.2 [M+H]⁺

Step C:9-(2-benzyl-3-oxo-6-(2-azaspiro[3.3]heptan-2-yl)-(2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

A solution of9-(2-benzyl-6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(0.100 g, 0.200 mmol) and 2-azaspiro[3.3]heptane hydrochloride (0.053 g,0.40 mmol) in dioxane (6 mL) was stirred with argon purging for tenminutes. Cs₂CO₃ (0.195 g, 0.600 mmol) was added to the reaction mixtureunder argon purging followed by the addition of Pd₂(dba)₃ (30 mg, 0.040mmol) and JohnPhos (10 mg, 0.040 mmol). The mixture was heated at 100°C. for 16 h. After cooling to RT, water was added to the reactionmixture and it was extracted with EtOAc, washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationby silica gel chromatography (60-70% EtOAc:hexane) provided the titlecompound as a white solid (0.068 g, 0.12 mmol). ¹H NMR (400 MHz,chloroform-d) δ 7.46-7.34 (m, 2H), 7.24-7.09 (m, 2H), 6.95-6.82 (m, 1H),6.82-6.69 (m, 1H), 5.64 (s, 1H), 5.09 (s, 2H), 3.9-4.05 (m, 3H), 3.8 (s,3H), 2.65-2.75 (m, 2H), 2.58-2.61 (m, 2H), 2.14 (t, 3H), 1.98-2.12 (m,4H), 1.8-1.92 (m, 4H), 1.7-1.78 (m, 3H); m/z=560.3 [M+H]⁺; t_(R)=1.64min (LCMS method j)

Example 11:1-(3,4-difluorophenyl)-9-(6-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecane-2-one

9-(6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(0.200 g, 0.489 mmol) and 4-fluorophenylboronic acid (0.342 g, 2.45mmol) were stirred in dioxane (5 mL) and H₂O (2 mL) at RT under argonpurging for 10 min. K₃PO₄ (0.311 g, 1.47 mmol) was added to the reactionmixture under argon purging followed by the addition of XPhosPd G2 (77mg, 0.097 mmol). The mixture was refluxed at 110° C. for 48 h. Aftercooling to RT, water was added to the reaction mixture and it wasextracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. Purification by preparativeHPLC (LUNA Phoenomenex, 5 μm, 21.2×250 mm; H₂O:MeCN elution) providedthe title compound (60 mg, 0.13 mmol) as an off-white solid. ¹H NMR (400MHz, chloroform-d) δ 11.19 (s, 1H), 7.68 (dd, 2H), 7.09-7.25 (m, 3H),6.92 (t, 1H), 6.82 (d, 1H), 6.61 (s, 1H), 4.21 (brs, 2H), 2.91 (t, 2H),2.62 (t, 2H), 2.10-2.19 (m, 2H), 2.03 (m, 2H), 1.93 (m2H), 1.83 (d, 2H);m/z=469.1 [M+H]⁺; t_(R)=1.47 min (LCMS method j).

Example 12:1-(3,4-difluorophenyl)-9-(3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5] undecane-2-one

Step A:6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazine-3-amine

A mixture of 6-chloropyridazin-3-amine (1.0 g, 0.77 mmol),4-(trifluorophenyl)-1H-pyrazole (0.210 g, 15.4 mmol) and Cs₂CO₃ (0.754g, 2.32 mmol) in dioxane (4 mL) were heated at 120° C. for 12 h. Aftercooling to RT, water was added to the reaction mixture and it wasextracted with EtOAc. The extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationby silica gel chromatography (35-40% EtOAC:hexane) provided6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazine-3-amine(0.400 g, 1.73 mmol). m/z=230.1 [M+H]⁺

Step B: 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3(2H)-one

A mixture of6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazine-3-amine(0.020 g, 0.087 mmol), NaNO₂ (0.012 g, 0.471 mmol) and concentratedH₂SO₄ (0.5 mL) in AcOH (1 mL) was heated at 80° C. for 16 h. Aftercooling to RT, water was added to the reaction mixture and it wasextracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. Purification by silica gelchromatography (40-50% EtOAC:hexane) provided6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3(2H)-one (0.010 g,0.43 mmol). m/z=231.0 [M+H]⁺

Step C:4-bromo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3(2H)-one

A mixture of 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3(2H)-one(0.20 g, 0.87 mmol), KOAc (0.640 g, 6.73 mmol) and Br₂ (7.0 mL, 7.4mmol) in AcOH (2 mL) was heated at 80° C. for 24 h. After cooling to RT,water was added to the reaction mixture and it was extracted with EtOAc.The extracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide crude4-bromo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3(2H)-one (170mg) which was used in the next step without purification. ¹H NMR (400MHz, methanol-d₄) δ 8.77 (s, 1H), 8.62 (s, 1H), 8.06 (s, 1H). m/z=311.0[M+2]⁺.

Step D:1-(3,4-difluorophenyl)-9-(3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5] undecane-2-one

1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one (IntermediateA, 0.090 g, 0.32 mmol),4-bromo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2-pyridazine-3(2H)-one(0.170 g, 0.550 mmol) and DIPEA (0.13 mL, 0.75 mmol) in DMF (3 mL) wererefluxed at 80° C. for 12 hours. After cooling to RT, the reactionmixture was diluted with cold water, extracted with EtOAc, washed withbrine, and dried over Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure to provide the title compound (85mg, 0.17 mmol). ¹H NMR (300 MHz, DMSO-d6) δ 12.8 (s, 1H), 8.88 (s, 1H),8.22 (s, 1H), 7.46 (m, 1H), 7.29 (m, 1H), 6.9 (m, 2H), 4.16 (d, 2H),2.96 (t, 2H), 2.41 (m, 2H), 2.04-2.18 (m, 2H), 1.83-1.91 (m, 4H),1.61-1.76 (m, 2H); m/z=509.15 [M+H]⁺; t_(R)=1.50 min (LCMS method j)

Example 13:1-(3,4-difluorophenyl)-9-(3-oxo-6-(2,2,2-trifluoroethoxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

This compound was synthesized analagously to Example 12 using2,2,2-trifluoroethan-1-ol. ¹H NMR (400 MHz, DMSO-d6) δ 12.1 (s, 1H),7.41 (m, 1H), 7.22 (m, 1H), 6.92 (m, 1H), 6.15 (s, 1H), 4.62-4.78 (m,2H), 4.01-4.12 (m, 2H), 2.74-2.88 (m, 2H), 2.41 (t, 2H), 2.07 (brs, 2H),1.78-1.88 (m, 4H), 1.54-1.7 (m, 2H); m/z=473.4 [M+H]⁺; t_(R)=0.66 min(LCMS method i)

Example 14:1-(3,4-difluorophenyl)-9-(2-methyl-3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecane-2-one

Iodomethane (0.018 g, 0.129 mmol) was added dropwise to a stirredsolution of1-(3,4-difluorophenyl)-9-(3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecane-2-one(0.040 g, 0.078 mmol) and Cs₂CO₃ (0.084 g, 0.259 mmol) in DMF (4 mL)cooled to 0° C. The reaction mixture was allowed to warm to RT over 4 h.Water was added to the reaction mixture and it was extracted with EtOAc,washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to provide the title compound (25 mg, 0.48 mmol). ¹H NMR (300MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.24 (s, 1H), 7.48 (m, 1H), 7.29 (m, 1H),6.92-7 (m, 2H), 4.12 (d, 2H), 3.6 (s, 3H), 2.98 (t, 2H), 2.42 (t, 2H),2.08 (brs, 2H), 1.7-1.92 (m, 4H), 1.68 (t, 2H); m/z=523.3 [M+H]⁺;t_(R)=1.64 min (LCMS method l).

Example 15a:1-(3,4-difluorophenyl)-9-(3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

and

Example 15b:9-(1-benzyl-6-oxo-3-((tetrahydro-2H-pyran-4-yl)oxy)-1,6-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 1-benzyl-5-bromo-1,2-dihydropyridazine-3,6-dione and1-benzyl-4-bromo-1,2-dihydropyridazine-3,6-dione

A mixture of 3-bromofuran-2,5-dione (5 g, 28.25 mmol) and benzylhydrazine.2HCl (8.20 g, 42.4 mmol) in water (45 mL) was heated at 100°C. for 16 h. The reaction mixture was cooled to RT and filtered. Theclear filtrate was concentrated under reduced pressure to provide acrude mixture of regioisomeric products (4.4 g, crude). m/z=283 [M+2]⁺

Step B:2-benzyl-4-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridazin-3(2H)-oneand2-benzyl-5-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridazin-3(2H)-one

A stirred solution of 1-benzyl-5-bromo-1,2-dihydropyridazine-3,6-dioneand 1-benzyl-4-bromo-1,2-dihydropyridazine-3,6-dione (2.00 g, 7.14 mmol)in DMF (25 mL) was treated with 4-bromo-tetrahydropyran (1.70 g, 10.3mmol) and K₂CO₃ (2.90 g, 20.9 mmol). The reaction mixture was heated at85° C. for 48 h. After cooling the reaction mixture was diluted withwater and extracted with EtOAc twice. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure to provide the mixture of regioisomeric products aswhite sticky solid (0.576 g, 1.58 mmol). m/z=367.0 [M+H]⁺

Step-C:9-(1-benzyl-6-oxo-3-((tetrahydro-2H-pyran-4-yl)oxy)-1,6-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-oneand9-(2-benzyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of2-benzyl-4-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridazin-3(2H)-oneand2-benzyl-5-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridazin-3(2H)-one(100 mg, 0.273 mmol) in DMF (2 mL) was treated with1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (Intermediate A,77 mg, 0.27 mmol) and DIPEA (72 μL, 0.41 mmol). The reaction mixture washeated at 80° C. for 48 h. After coolling to RT, the reaction mixturewas diluted with water and extracted with EtOAc twice. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude material was purified bypreparative HPLC (YMC, 5 μm, 21.2×150 mm; 0.02% aqueous NH₄OH:MeCNelution) to separate the two regioisomeric products:

Example 15a:9-(2-benzyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one,isolated as a pale yellow solid (115 mg, 0.203 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ 7.3-7.47 (m, 1H), 7.22-7.30 (m, 6H), 6.94-6.96 (m, 1H), 6.08(s, 1H), 5.03 (s, 2H), 4.72-4.81 (m, 1H), 3.9-4.05 (brs, 2H), 3.74-3.82(m, 2H), 3.41 (t, 2H), 2.78 (t, 2H), 2.41 (t, 2H), 2.08 (m, 2H),1.82-1.92 (m, 6H), 1.6-1.71 (m, 2H), 1.48-1.56 (m, 2H); m/z=565.2[M+H]+; t_(R)=1.71 min (LCMS method l).

Example 15b:9-(1-benzyl-6-oxo-3-((tetrahydro-2H-pyran-4-yl)oxy)-1,6-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one:¹H NMR (300 MHz, DMSO-d₆) δ 7.4-7.48 (m, 1H), 7.2-7.34 (m, 6H),6.84-6.89 (m, 1H), 5.92 (s, 1H), 4.96 (s, 2H), 4.77-4.84 (m, 1H),3.52-3.63 (m, 4H), 3.38-3.47 (m, 2H), 2.86 (t, 2H), 2.40 (t, 3H), 2.07(m, 2H), 1.75-1.9 (m, 5H), 1.58-1.72 (m, 2H), 1.4-1.53 (m, 2H),m/z=565.4 [M+H]+, t_(R)=2.13 min (LCMS method l);

Example 16:1-(3,4-difluorophenyl)-9-(3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of9-(2-benzyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(100 mg, 0.177 mmol) in EtOH (15 mL) was treated with Pd(OH)₂ (200 mg)and stirred under an atmosphere of H₂ (1 atm) for 48 h. The reactionmixture was flushed with nitrogen, filtered through a bed of celite, andthe filtrate concentrated under reduced pressure. Purification bypreparative HPLC (LUNA OMEGA C18, 5.0 μm, 21.2×250 mm; water:MeCNelution) afforded the the title compound as an off-white solid (40 mg,0.084 mmol). ¹H NMR (300 MHz, DMSO-d₆) δ 11.84 (s, 1H), 7.4-7.46 (m,1H), 7.10-7.15 (m, 1H), 6.95-7.0 (m, 1H), 6.02 (s, 1H), 4.70-4.82 (m,1H), 4.01 (d, 1H), 3.76-3.83 (m, 1H), 3.50-3.38 (m, 2H), 3.29-3.21 (m,1H), 2.76 (t, 2H), 2.01-2.11 (m, 2H), 1.72-1.98 (m, 8H), 1.52-1.7 (m,5H); m/z=475.4 [M+H]⁺; t_(R)=0.45 min (LCMS method l).

Example 17:1-(3,4-difluorophenyl)-9-(2-methyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of of1-(3,4-difluorophenyl)-9-(3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one(30 mg, 0.063 mmol), Cs₂CO₃ (61 mg, 0.19 mmol) and iodomethane (6 μL,0.096 mmol) in DMF (1 mL) was stirred at RT for 16 h. The reactionmixture was diluted with water and extracted with EtOAc twice. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification bypreparative HPLC (ZORBAX, 5 μm, 21.2×150 mm; water:ACN elution) affordedthe the title compound (8 mg, 0.016 mmol) as an off-white solid. ¹H NMR(400 MHz, chloroform-d) δ 7.68 (dd, 1H), 7.10-7.15 (m, 1H), 6.96-7.0 (m,1H), 6.05 (s, 1H), 4.72-4.84 (m, 1H), 3.92-4.2 (m, 2H), 3.38-3.47 (m,4H), 2.77 (t, 2H), 2.4 (t, 2H), 2.06 (d, 2H), 1.9-2.0 (m, 2H), 1.8-1.84(m, 4H), 1.52-1.68 (m, 4H); m/z=489.2 [M+H]⁺; t_(R)=1.3 min (LCMS methodk).

Example 18:9-(6-(4,4-difluorocyclohex-1-en-1-yl)-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

Step A:9-(6-bromo-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one (IntermediateA, 0.870 g, 3.10 mmol), 5-bromo-3-chloropyrazin-2(1H)-one (0.650 g, 3.10mmol) and DIPEA (1.6 mL, 9.3 mmol) in EtOH (10 mL) were heated at 80° C.for 12 h. The reaction mixture was diluted with water and extracted withEtOAc twice. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by silica gel chromatography (2-8% MeOH in DCM) provided9-(6-bromo-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-oneas a white solid (0.460 g, 1.01 mmol). m/z=455.05 [M+H]⁺

Step B:9-(6-(4,4-difluorocyclohex-1-en-1-yl)-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

A mixture of9-(6-bromo-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(0.050 g, 0.110 mmol) and2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.081 g, 0.331 mmol) were stirred in DME (1 mL) and H₂O (0.5 mL) at RTunder argon purging for 10 minutes. K₂CO₃ (0.046 g, 0.33 mmol) was addedto the reaction mixture under argon purging followed by the addition ofPd(dppf)Cl₂.DCM (0.018 g, 0.022 mmol). The mixture was heated at 100° C.for 16 h. After cooling to RT, the reaction mixture was diluted withwater and extracted with EtOAc twice. The extracts were washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purification by preparative HPLC (LUNA C18, 5 μm, 21.2×250 mm;water:ACN elution) provided the title compound (21 mg, 0.043 mmol) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 7.44 (m, 1H),7.25 (ddd, 1H), 6.93 (m, 1H), 6.75 (s, 1H), 6.24 (s, 1H), 4.50 (d, 2H),2.85 (m, 2H), 2.67 (m, 2H), 2.41 (m, 4H), 2.09 (m, 4H), 1.91-1.77 (m,4H), 1.63 (m, 2H). m/z=491.2 [M+H]⁺; t_(R)=1.49 min (LCMS method j).

Example 19:9-(6-(4,4-difluorocyclohex-1-en-1-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

Step A:9-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate A, 0.630 g, 2.24 mmol),3,5-dibromo-1-methylpyrazin-2(1H)-one (0.600 g, 2.24 mmol) and DIPEA(1.2 mL, 6.7 mmol) in EtOH (8 mL) were heated at 80° C. for 12 h. Aftercooling to RT, the reaction mixture was diluted with water and extractedwith EtOAc twice. The extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationby silica gel chromatogrpahy (2-7% MeOH in DCM) provided9-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-oneas a light brown solid (0.770 g, 1.65 mmol). m/z=469.05 [M+2]⁺

Step B:9-(6-(4,4-difluorocyclohex-1-en-1-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

9-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(0.310 g, 0.660 mmol) and2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.200 g, 0.820 mmol) were stirred in DME (2.5 mL) and water (1 mL) atRT under argon purging for 10 min. K₂CO₃ (0.177 g, 1.28 mmol) was addedto the reaction mixture under argon purging followed by the addition ofPd(dppf)Cl₂-DCM (0.070 g, 0.086 mmol). The mixture was heated at 100° C.for 16 h. After cooling to RT, the reaction mixture was diluted withwater and extracted with EtOAc twice. The combined extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purification by preparative HPLC (Waters ATLANTIS C18.5 μm,21.2×250 mm; water/(1:1 ACN/MeOH) elution) provided the title compound(0.118 g, 0.233 mmol) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.42-7.47 (m, 1H), 7.2-7.28 (m, 1H), 7.16 (s, 1H), 6.88-6.92 (m, 1H),6.2 (m, 1H), 4.46 (d, 2H), 3.32 (s, 3H), 2.88 (t, 2H), 2.68 (t, 2H),2.49-2.51 (m, 1H), 2.39-2.43 (m, 4H), 2.07-2.18 (m, 4H), 1.81-1.84 (m,3H), 1.58-1.68 (m, 2H); m/z=505.2 [M+H]⁺; t_(R)=1.59 min (LCMS methodk).

Example 20:1-(4-chloro-3-fluorophenyl)-9-(5-cyclopentyl-1,2,4-triazin-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 2-cyclopentyl-2-oxoacetaldehyde

A mixtue of 1-cyclopentylethanone (236 mg, 2.10 mmol) and seleniumdioxide (244 mg, 2.20 mmol) in 1 mL of dioxane and 0.1 mL of water wasstirred overnight at 80° C. The dark-brown reaction mixture was filteredover cotton wool and washed with 4 mL of water. The filtrate was usedwithout further purification in the next step.

Step B: 5-cyclopentyl-3-(methylthio)-1,2,4-triazine

Sodium bicarbonate (168 mg, 2.00 mmol) was added to the reaction mixtureof the previous step. The white suspension was cooled to 0-5° C. and asolution of methyl hydrazinecarbimidothioate hydroiodide (373 mg, 1.60mmol) in 2 mL of water was added. The reaction mixture was stirred for 2h at 0-5° C. and then diluted with DCM and water. The organic layerswere dried over Na₂SO₄, filtered, and concentrated. The crude productwas adsorbed onto silica gel and purified by silica gel chromatography(0-50% EtOAc in cyclohexane). m/z=196.2 [M+H]⁺; t_(R)=1.02 min (LCMSmethod a).

Step C:1-(4-chloro-3-fluorophenyl)-9-(5-cyclopentyl-1,2,4-triazin-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

MCPBA (134 mg, 0.584 mmol) was added to a solution of5-cyclopentyl-3-(methylthio)-1,2,4-triazine (100 mg, 0.486 mmol) DMF (1mL) cooled to 0° C. The reaction mixture was allowed to warm to RT andwas stirred for 1.5 h. Triethylamine (340 μL, 2.43 mmol) and1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 144 mg, 0.486 mmol) were added and the mixture wasstirred at RT for two days. The solution was quenched with ice water,extracted with DCM, and the extracts were concentrated. The crudeproduct was adsorbed onto silica gel and purified by silica gelchromatography (0-50% EtOAc in cyclohexane) followed by SFC (Princeton4-ethylpyridine 100 Å, 30×250 mm, 5 μm; 9-14% MeOH in CO₂, 10 min) toprovide the title compound (28 mg, 0.060 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ=8.54 (s, 1H), 7.58 (dd, 1H), 7.23 (d, 1H), 6.96 (d, 1H), 4.54(m, 1H), 4.08 (m, 2H), 3.18 (m, 4H), 3.05 (m, 3H), 2.45 (t, 2H), 2.18(m, 2H), 1.9 (m, 4H), 1.5-1.7 (m, 5H) ppm; m/z=444.2 [M+H]⁺; t_(R)=1.16min (LCMS method a).

Example 21:1-(4-chloro-3-fluorophenyl)-9-(5-(4-fluorophenyl)oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 5-(4-fluorophenyl)oxazole

Tosylmethylisocyanate (787 mg, 3.95 mmol) and K₂CO₃ (655 mg, 4.74 mmol)were added to a solution of 4-fluorobenzaldehyde (0.425 mL, 3.95 mmol)in 20 mL of MeOH. The reaction mixture was stirred for 3 h at 80° C.,then 16 h at RT. The reaction mixture was concentrated, diluted withwater and extracted three times with ethyl acetate. The organic extractswere dried over Na₂SO₄, filtered, and concentrated. Purification bysilica gel chromatography (10-60% EtOAc in cyclohexane) provided5-(4-fluorophenyl)oxazole (539 mg, 3.14 mmol). ¹H NMR (600 MHz, DMSO-d₆)δ=8.45 (s, 1H), 7.78 (m, 2H), 7.68 (s, 1H), 7.34 (m, 2H) ppm; m/z=164.1[M+H]⁺; t_(R)=0.88 min (LCMS method d).

Step B: 2-chloro-5-(4-fluorophenyl)oxazole

LiHMDS (1.0 M in THF, 1.53 mL, 1.53 mmol) was added dropwise to asolution of 5-(4-fluorophenyl)oxazole (200 mg, 1.23 mmol) in 10 mL ofTHF cool to −78° C. The reaction mixture was stirred for 30 min at −78°C. This solution was then added dropwise to a suspension ofhexachloroethane (580 mg, 2.45 mmol) in 5 mL of THF at −78° C. Thereaction mixture was allowed to warm up to RT and was further stirred atthis temperature for 12 h. The mixture was quenched with saturatedaqueous NH₄Cl and extracted twice with EtOAc. The combined extracts weredried over Na₂SO₄, filtered, and concentrated. The crude product waspurified by silica gel chromatography (50-100% DCM in cyclohexane) toprovide 2-chloro-5-(4-fluorophenyl)oxazole (61 mg, 0.31 mmol). ¹H NMR(600 MHz, DMSO-d₆) δ=7.78 (s, 1H), 7.75 (m, 2H), 7.36 (m, 2H) ppm;m/z=molecular ion not detected; t_(R)=1.09 min (LCMS method a).

Step C:1-(4-chloro-3-fluorophenyl)-9-(5-(4-fluorophenyl)oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 2-chloro-5-(4-fluorophenyl)oxazole (57 mg, 0.288 mmol),triethylamine (0.11 mL, 0.81 mmol) and1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 80 mg, 0.27 mmol) in 4 mL of EtOH was stirred for 3 hat 160° C. After cooling to RT the reaction was concentrated, dilutedwith ethyl acetate, and washed with brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated. Purification by SFC (Princeton2-ethylpyridine 100 Å, 5 μm, 30×250 mm; 13-18% MeOH in CO₂, 13 min)provided the title compound (76 mg, 0.17 mmol) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ=7.61 (dd, 1H), 7.54 (dd, 2H), 7.27 (dd, 1H), 7.24(s, 1H), 7.22 (dd, 2H), 6.98 (dd, 1H), 4.89 (m, 2H), 3.17 (m, 2H), 2.43(t, 2H), 2.11 (m, 2H), 1.88 (m, 2H), 1.84 (m, 2H), 1.61 (m, 2H) ppm;m/z=458.3 [M+H]⁺; t_(R)=1.12 min (LCMS method a).

Example 22:1-(4-chloro-3-fluorophenyl)-9-(2-phenyl-2H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A:1-(4-chloro-3-fluorophenyl)-9-(1H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of sodium azide (515 mg, 7.92 mmol), triethylaminehydrochloride (1.09 g, 7.92 mmol) and1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carbonitrile(850 mg, 2.64 mmol) in 10 mL of DMF was heated under microwaveirradiation for 2 h at 130° C. The reaction mixture was filtered,diluted with EtOAc and the pH was adjusted to 5 by addition of 4 N HCl.The aqueous layer was extracted twice with EtOAc. The combined organicextracts were dried over Na₂SO₄, filtered and concentrated. Purificationby silica gel chromatography (0-30% MeOH in DCM) provided1-(4-chloro-3-fluorophenyl)-9-(1H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one.¹H NMR (400 MHz, DMSO-d₆) δ=14.95 (br s, 1H), 7.60 (dd, 1H), 7.26 (d,1H), 6.98 (dd, 1H), 3.67 (m, 2H), 3.17 (t, 2H), 2.43 (t, 2H), 2.09 (m,2H), 1.8-1.88 (m, 4H), 1.62 (m, 2H) ppm; m/z=365.2 [M+H]⁺; t_(R)=0.65min (LCMS method a).

Step C:1-(4-chloro-3-fluorophenyl)-9-(2-phenyl-2H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

K₂CO₃ (62.5 mg, 0.452 mmol), [Cu(OH)(TMEDA)]₂Cl₂ (23 mg, 0.049 mmol) andphenyl boronic acid (158 mg, 1.23 mmol) were added under argon to asolution of1-(4-chloro-3-fluorophenyl)-9-(1H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 150 mg, 0.411 mmol) in 3 mL of DCM. The resultingmixture was momentarily placed under vacuum before adding an O₂ balloonand stirred at RT for 48 h. The reaction mixture was filtered throughcelite and concentrated. Purification by silica gel chromatography (0-5%MeOH in DCM) provided the title compound (32 mg, 0.070 mmol). ¹H NMR(400 MHz, DMSO-d₆) δ=7.93 (d, 2H), 7.58-7.62 (m, 3H), 7.51 (t, 1H), 7.26(dd, 1H), 6.98 (d, 1H), 3.90 (m, 2H), 3.17-3.19 (m, 2H), 2.45 (t, 2H),2.13 (m, 2H), 1.86-1.95 (m, 4H), 1.6-1.75 (m, 2H) ppm; m/z=441.2 [M+H]⁺;t_(R)=1.19 min (LCMS method a).

Example 23:1-(4-chloro-3-fluorophenyl)-9-(5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 3-chloro-5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazole

A mixture of 3,5-dichloro-1,2,4-thiadiazole (150 mg, 0.968 mmol),3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol) andtriethylamine (0.67 mL, 4.8 mmol) in EtOH (1.5 mL) was stirred for 1 hat RT. The reaction was diluted with EtOAc and washed with water. Theorganic layer was dried over Na₂SO₄, filtered, and evaporated.Purification by silica gel chromatography (0-15% EtOAc in cyclohexane)provided 3-chloro-5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazole (165mg, 0.731 mmol) as a white crystalline solid. ¹H NMR (400 MHz, DMSO-d₆)δ=3.95 (t, 2H), 3.70 (m, 2H), 2.6-2.7 (m, 2H) ppm; m/z=226.0 [M+H]⁺;t_(R)=0.84 min (LCMS method a).

Step B:1-(4-chloro-3-fluorophenyl)-9-(5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 100 mg, 0.337 mmol),3-chloro-5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazole (114 mg,0.505 mmol) and triethylamine (0.14 mL, 1.0 mmol) in DMF (1.5 mL) washeated under microwave irradiation for 3 h at 160° C. After cooling toRT, the reaction mixture was diluted with EtOAc and washed with water.The organic layer was dried over Na₂SO₄, filtered, and concentrated.Purification by SFC (Waters Atlantis HILIC silica, 30×250 mm, 5 μm,11-16% MeOH in CO₂, 10 min) provided the title compound (29 mg, 0.059mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.60 (t, 1H), 7.23 (dd, 1H), 6.95(dd, 1H), 4.05 (m, 2H), 3.8 (m, 2H), 3.55 (t, 2H), 3.0 (m, 2H), 2.55 (m,2H), 2.45 (t, 2H), 2.1 (m, 2H), 1.8-1.9 (m, 4H), 1.45-1.6 (m, 2H) ppm;m/z=486.2 [M+H]⁺; t_(R)=1.10 min (LCMS method a).

By employing similar methods as described for the preparation of Example23, using appropriate starting materials, the following compounds wereprepared:

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 24

504.1; 1.14 min, LCMS method a ¹H NMR (400 MHz, DMSO-d₆) δ = 7.62 (t,1H), 7.23 (dd, 1H), 6.95 (d, 1H), 4.25 (t, 2H), 4.0- 4.1 (m, 4H), 3.8(m, 1H), 3.01 (m, 2H), 2.43 (t, 2H), 2.10 (m, 2H), 1.80-1.85 (m, 4H),1.56 (m, 2H) ppm 25

450.5; 1.09 min, LCMS method a ¹H NMR (400 MHz, DMSO-d₆) δ = 7.62 (t,1H), 7.23 (dd, 1H), 6.95 (d, 1H), 4.09 (m, 2H), 3.25 (m, 4H), 3.00 (m,2H), 2.45 (t, 2H), 2.10 (m, 2H), 1.93 (m, 4H), 1.8 (m, 4H), 1.51 (m, 2H)ppm

Example 26:1-(4-chloro-3-fluorophenyl)-9-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: bis(1H-benzo[d][1,2,3]triazol-1-yl)methanimine

Benzotriazole (5.96 g, 50 mmol) was dissolved in EtOH (100 mL) andstirred at 0° C. A solution of BrCN (2.656 g, 25 mmol) in 10 mL ofacetone was added followed by aqueous NaOH (8.0 M, 3.1 mL, 25 mmol). Theresulting suspension was stirred for 20 min at 0° C. The whiteprecipitate was filtered off, washed with ice cold EtOH, and dried underreduced pressure to provide crudebis(1H-benzo[d][1,2,3]triazol-1-yl)methanimine. m/z=264.2 [M+H]⁺;t_(R)=0.92 min (LCMS method a).

Step B:9-((1H-benzo[d][1,2,3]triazol-1-yl)(imino)methyl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A suspension of1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 100 mg, 0.337 mmol) in THF (1 mL) was added dropwise toa suspension of bis(1H-benzo[d][1,2,3]triazol-1-yl)methanimine in dryTHF (2.5 mL). The reaction mixture was stirred overnight at RT, dilutedwith DCM, washed with Na₂CO₃ solution, dried over Na₂SO₄, filtered andconcentrated. The crude product was used in the next step withoutfurther purification. m/z=441.2 [M+H]⁺; t_(R)=0.65 min (LCMS method a).

Step C:(E)-N-((1H-benzo[d][1,2,3]triazol-1-yl)(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)methylene)-4-fluorobenzamide

4-fluorobenzoyl chloride (37 mg, 0.23 mmol) and TEA (32 μL, 0.23 mmol)were added to a solution of9-((1H-benzo[d][1,2,3]triazol-1-yl)(imino)methyl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(170 mg, 0.231 mmol) in DCM (2.5 mL). The resulting mixture was stirredovernight at RT, diluted with DCM and washed with water. The organiclayer was dried over Na₂SO₄, filtered, and concentrated. Purification bysilica gel chromatography (0-100% EtOAc in cyclohexane followed by 0-10%MeOH in DCM) provided(E)-N-((1H-benzo[d][1,2,3]triazol-1-yl)(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)methylene)-4-fluorobenzamide(31 mg, 0.05 mmol). m/z=563.3 [M+H]⁺; t_(R)=1.10 min (LCMS method a).

Step D:1-(4-chloro-3-fluorophenyl)-9-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Hydrazine (1.0 M in THF, 0.06 mL, 0.06 mmol) was added to a solution of(E)-N-((1H-benzo[d][1,2,3]triazol-1-yl)(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)methylene)-4-fluorobenzamide(34 mg, 0.06 mmol) in DCM (0.5 mL). After stirring overnight at RT,additional hydrazine (1.0 M in THF, 0.06 mL, 0.06 mmol) was added andstirring was continued for an additional hour. The reaction mixturediluted with DCM, washed with aqueous Na₂CO₃, dried over Na₂SO₄,filtered and concentrated. Purification by silica gel chromatography(0-20% MeOH in DCM) provided the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ=12.55 (s, 1H), 7.90 (dd, 2H), 7.60 (t, 1H), 7.24 (m, 3H),6.98 (d, 1H), 3.75 (m, 2H), 3.0 (m, 2H), 2.43 (t, 2H), 2.10 (m, 2H),1.85 (m, 4H), 1.63 (m, 2H) ppm; m/z=458.2 [M+H]⁺; t_(R)=0.96 min (LCMSmethod a).

Example 27:1-(4-chloro-3-fluorophenyl)-9-(5-cyclohexyloxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

Methanesulfonic acid (0.017 mL, 0.26 mmol) was added to a mixture of1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carbonitrile(140 mg, 0.435 mmol), 2-picoline N-oxide (47 mg, 0.44 mmol), Ph₃PAuNTf₂(2:1 toluene adduct, 17 mg, 0.019 mmol) and ethynylcyclohexane (0.028mL, 0.218 mmol) in 2 mL of chlorobenzene. The reaction mixture wasstirred for 16 h at 60° C. After cooling to RT, the mixture was dilutedwith DCM and washed with 5% K₂CO₃ solution and brine. The organic layerwas dried over Na₂SO₄, filtered, and concentrated. Purification bysilica gel chromatography (0-10% MeOH in DCM) followed by SFC(Reprospher PEI 100 Å, 5 um, 30×250 mm; 7-17% MeOH in CO₂, 10 min)provided the title compound (7 mg, 0.012 mmol). ¹H NMR (600 MHz,DMSO-d₆) δ=7.60 (dd, 1H), 7.23 (dd, 1H), 6.95 (d, 1H), 6.33 (d, 1H),3.68 (m, 2H), 3.03 (t, 2H), 2.41 (t, 2H), 2.07 (m, 2H), 1.80-1.84 (m,5H), 1.56-1.67 (m, 6H), 1.15-1.29 (m, 6H) ppm; m/z=446.4 [M+H]⁺;t_(R)=1.23 min (LCMS method a).

Example 28:1-(4-chloro-3-fluorophenyl)-9-(5-phenyl-1,3,4-oxadiazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 5-phenyl-1,3,4-oxadiazole-2-thiol (54 mg, 0.303 mmol) and1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 90 mg, 0.30 mmol) in EtOH (0.8 mL) was heated undermicrowave irradiation for 8 h at 160° C. After cooling to RT thereaction mixture was concentrated. Purification by SFC (Reprosphere PEI100 Å, 30×250, 5 μm, 11-16% MeOH in CO₂, 10 min) provided the titlecompound (33 mg, 0.071 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=7.82-7.86 (m,2H), 7.61 (t, 1H), 7.51 (m, 3H), 7.26 (dd, 1H), 6.99 (d, 1H), 3.83 (m,2H), 3.29 (m, 2H), 2.45 (t, 2H), 2.13 (m, 2H), 1.95 (m, 2H), 1.86 (m,2H), 1.68 (m, 2H) ppm; m/z=441.2 [M+H]⁺; t_(R)=0.99 min (LCMS method a).

Example 29:1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 1-(4-fluorophenyl)-1H-1,2,3-triazole

Propiolic acid (0.20 mL, 3.3 mmol), sodium ascorbate (174 mg, 0.875mmol), DBU (0.17 mL, 1.1 mmol) and copper(I) iodide (83 mg, 0.44 mmol)were added to a solution of 1-azido-4-fluorobenzene (4.38 mL, 2.19 mmol)in DMF (10 mL). The reaction mixture was stirred for 3 h at 60° C.,cooled to RT, diluted with EtOAc and washed with water. The organiclayer was dried over Na₂SO₄ and concentrated. Purification by silica gelchromatography (20-70% EtOAc in cyclohexane) provided1-(4-fluorophenyl)-1H-1,2,3-triazole (295 mg, 1.77 mmol) as a yellowsolid. ¹H NMR (600 MHz, DMSO-d₆) δ=8.82 (d, 1H), 7.98 (d, 1H), 7.97-7.91(m, 2H), 7.48-7.45 (m, 2H) ppm; m/z=164.1 [M+H]⁺; t_(R)=0.70 min (LCMSmethod a).

Step B: 1-(4-fluorophenyl)-1H-1,2,3-triazole 3-oxide

MCPBA (402 mg, 2.33 mmol) was added to a solution of1-(4-fluorophenyl)-1H-1,2,3-triazole (292 mg, 1.79 mmol) in EtOAc (2mL). The reaction mixture was stirred for 72 h at RT. The mixture wasdiluted with DCM and washed with 1 M NaOH. The organic layer was driedover Na₂SO₄ and concentrated. Purification by silica gel chromatography(80-100% EtOAc in cyclohexane, followed by 0-20% MeOH in DCM) provided1-(4-fluorophenyl)-1H-1,2,3-triazole 3-oxide (177 mg, 0.988 mmol) as awhite solid. ¹H NMR (600 MHz, DMSO-d₆) δ=8.92 (d, 1H), 7.94 (d, 1H),7.87-7.80 (m, 2H), 7.50-7.42 (m, 2H) ppm; m/z=180.1 [M+H]⁺; t_(R)=0.46min (LCMS method a).

Step C: 4-bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole 3-oxide

Bromine (0.204 mL, 3.95 mmol) was added dropwise to a solution of1-(4-fluorophenyl)-1H-1,2,3-triazole 3-oxide (177 mg, 0.988 mmol) andNa₂CO₃ (209 mg, 1.98 mmol) in a mixture of CHCl₃ (0.6 mL) and water (0.8mL) cooled to 0° C. The reaction mixture was stirred for 12 h at RT. A10% aqueous solution of sodium thiosulfate was added and stirringcontinued for 30 min at RT. The mixture was extracted three times withDCM. The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated. Purification by silica gel chromatography (0-6%MeOH in DCM) provided 4-bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole3-oxide (204 mg, 0.791 mmol) as a white crystalline solid. ¹H NMR (600MHz, DMSO-d₆) δ=9.24 (s, 1H), 7.85-7.78 (m, 2H), 7.52-7.43 (m, 2H) ppm.m/z=258.1, 260.1 [M+H]⁺; t_(R)=0.59 min (LCMS method a).

Step D: 4-bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole

PCl₃ (2.00 mL, 22.9 mmol) was added to4-bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole 3-oxide (200 mg, 0.775mmol) and the reaction mixture was stirred for 1 h at 80° C. The mixturewas quenched with water and extracted twice with DCM. The combinedorganic layers were dried over Na₂SO₄ and concentrated. The crude4-bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole obtained (177 mg) was usedin the next step without further purification. ¹H NMR (600 MHz, DMSO-d₆)δ=9.12 (s, 1H), 7.98-7.92 (m, 2H), 7.54-7.45 (m, 2H) ppm; m/z=242.1,244.1 [M+H]⁺; t_(R)=0.94 min (LCMS method a).

Step E:1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

4-bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole (80 mg, 0.329 mmol),BrettPhos Precat G1 (22.42 mg, 0.025 mmol) and sodium tert-butoxide(60.7 mg, 0.632 mmol) were added to a solution of1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 75 mg, 0.253 mmol) in dioxane (3 mL). The reactionmixture was heated under microwave irradiation for 2 h at 120° C.,cooled to RT, evaporated, diluted with EtOAc and washed with saturatedaqueous NaHCO₃ solution. The organic layer was dried over Na₂SO₄ andconcentrated. Purification by SFC (Princeton 4-ethylpyridine 60 Å,30×250 mm, 5 μm, 5-25% MeOH in CO₂, 17 min) provided the title compound(8 mg, 0.02 mmol) as a white solid. ¹H NMR (600 MHz, DMSO-d₆) δ=8.11 (s,1H), 7.87-7.81 (m, 2H), 7.62 (dd, 1H), 7.42 (dd, 2H), 7.27 (dd, 1H),7.00 (m, 1H), 3.55 (m, 2H), 2.87 (m, 2H), 2.43 (t, 2H), 2.08 (m, 2H),1.90-1.82 (m, 4H), 1.72 (m, 2H) ppm; m/z=458.1 [M+H]⁺; t_(R)=1.05 min(LCMS method a).

Example 30:1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 1-(4-fluorophenyl)-3-iodo-1H-pyrazole

1-Fluoro-4-iodobenzene (0.476 mL, 4.08 mmol), CuI (13 mg, 0.068 mmol),trans-N,N′-Dimethylcyclohexane-1,2-diamine (0.043 mL, 0.27 mmol) andK₂CO₃ (564 mg, 4.08 mmol) were added to a solution of3-bromo-1H-pyrazole (200 mg, 1.36 mmol) in toluene (12 mL). The reactionmixture was stirred for 72 h at 100° C., cooled to RT, concentrated,diluted with EtOAc and washed with brine. The organic layer was driedover Na₂SO₄ and concentrated. Purification by silica gel chromatography(0-20% EtOAc in cyclohexane) provided1-(4-fluorophenyl)-3-iodo-1H-pyrazole (204 mg, 0.673 mmol) as a paleyellow solid. ¹H NMR (600 MHz, DMSO-d₆) δ=8.40 (d, 1H), 7.83 (m, 2H),7.35 (m, 2H), 6.78 (d, 1H) ppm; m/z=289.1 [M+H]⁺; t_(R)=1.13 min (LCMSmethod a).

Step B:1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

1-(4-Fluorophenyl)-3-iodo-1H-pyrazole (93 mg, 0.323 mmol), BrettPhosPrecat G1 (24 mg, 0.027 mmol) and sodium tert-butoxide (78 mg, 0.81mmol) were added to a solution of1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 80 mg, 0.27 mmol) in dioxane (4 mL). The reactionmixture was heated under microwave irradiation for 12 h at 100° C.,cooled to RT, concentrated, diluted with EtOAc and washed with brine.The organic layer was dried over Na₂SO₄ and concentrated. Purificationby SFC (Reprospher PEI, 30×205 mm, 5 μm, 10-15% MeOH in CO₂, 10 min)provided the title compound (39 mg, 0.083 mmol) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ=8.21 (s, 1H), 7.67 (m, 2H), 7.61 (m, 1H), 7.24 (m,3H), 6.98 (m, 1H), 6.01 (s, 1H), 3.60 (m, 2H), 2.85 (t, 2H), 2.42 (m,2H), 2.07 (m, 2H), 1.85 (m, 4H), 1.67 (m, 2H) ppm; m/z=457.4 [M+H]⁺;t_(R)=1.21 min (LCMS method a).

Example 31:1-(4-chloro-3-fluorophenyl)-9-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 2-(4-fluorophenyl)-4-nitro-2H-1,2,3-triazole

(4-Fluorophenyl)boronic acid (6.13 g, 43.8 mmol), copper-(II)-acetate(5.97 g, 32.9 mmol) and pyridine (3.6 mL, 44 mmol) were added to asolution of 4-nitro-2H-1,2,3-triazole (2.50 g, 21.9 mmol) in DCE (70mL). The reaction mixture was stirred for 12 h at RT, filtered over abed of celite, diluted with DCM and washed with water, NaHCO₃ solutionand brine. The organic layer was dried over Na₂SO₄ and concentrated.Purification by silica gel chromatography (0-30% EtOAc in cyclohexane)provided 2-(4-fluorophenyl)-4-nitro-2H-1,2,3-triazole (930 mg, 4.47mmol) as a white solid. m/z=molecular ion not detected; t_(R)=1.05 min(LCMS method a).

Step B: 2-(4-fluorophenyl)-2H-1,2,3-triazol-4-amine

Acetic acid (2.6 mL, 45 mmol) and iron (1.25 g, 22.3 mmol) were added toa solution of 2-(4-fluorophenyl)-4-nitro-2H-1,2,3-triazole (930 mg, 4.47mmol) in THF (30 mL). The reaction mixture was stirred for 12 h at 80°C. Additional AcOH (2.56 mL, 44.7 mmol) and iron (500 mg, 8.95 mmol)were added and the mixture was stirred for 3 h at 80° C. The mixture wasfiltered over a bed of celite, diluted with EtOAc and washed withsaturated NaHCO₃ solution and brine. The organic layer was dried overNa₂SO₄ and concentrated. Purification by silica gel chromatography(0-56% EtOAc in cyclohexane) provided2-(4-fluorophenyl)-2H-1,2,3-triazol-4-amine (690 mg, 3.37 mmol) as awhite solid. ¹H NMR (600 MHz, DMSO-d₆) δ=7.80 (m, 2H), 7.32 (m, 2H),7.25 (s, 1H), 5.52 (br s, 2H) ppm; m/z=179.1 [M+H]⁺; t_(R)=0.80 min(LCMS method a).

Step C: 4-bromo-2-(4-fluorophenyl)-2H-1,2,3-triazole

A solution of 2-(4-fluorophenyl)-2H-1,2,3-triazol-4-amine (300 mg, 1.68mmol) in 7 mL of acetonitrile was added dropwise to a solution ofcopper-(II)-bromide (451 mg, 2.02 mmol) and tert-butyl nitrite (0.36 mL,2.7 mmol) in acetonitrile (7 mL). The reaction mixture was stirred for 2h at RT, diluted with EtOAc and washed with brine. The organic layer wasdried over Na₂SO₄ and concentrated. Purification by silica gelchromatography (0-24% EtOAc in cyclohexane) provided4-bromo-2-(4-fluorophenyl)-2H-1,2,3-triazole (330 mg, 1.27 mmol). ¹H NMR(600 MHz, DMSO-d₆) δ=8.35 (s, 1H), 8.01 (m, 2H), 7.43 (m, 2H) ppm;t_(R)=0.80 min (LCMS method a)

Step D:1-(4-chloro-3-fluorophenyl)-9-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

4-Bromo-2-(4-fluorophenyl)-2H-1,2,3-triazole (73.4 mg, 0.303 mmol),BrettPhos Precat G1 (29.9 mg, 0.034 mmol) and sodium tert-butoxide (81mg, 0.842 mmol) were added to a solution of1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 100 mg, 0.337 mmol) in dioxane (3 mL). The reactionmixture was heated under microwave irradiation for 3 h at 120° C.,cooled to RT, concentrated, diluted with EtOAc and washed with saturatedNaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄ andconcentrated. Purification by silica gel chromatography (50-100% EtOAcin cyclohexane, followed by 0-5% MeOH in EtOAc), then SFC (Reprosil NH2,5 μm, 30×250 mm; 18-23% MeOH in CO₂, 10 min) provided the title compound(8 mg, 0.02 mmol) as a white solid. ¹H NMR (600 MHz, DMSO-d₆) δ=7.83(dd, 2H), 7.61 (m, 2H), 7.32 (dd, 2H), 7.27 (dd, 1H), 6.99 (d, 1H), 3.62(m, 2H), 2.98 (m, 2H), 2.43 (t, 2H), 2.09 (m, 2H), 1.82-1.88 (m, 4H),1.66-1.72 (m, 2H) ppm; m/z=458.3 [M+H]⁺; t_(R)=1.27 min (LCMS method a).

Example 32:1-(4-chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 2-chloro-6-(4-fluorophenyl)pyridine

2-Bromo-6-chloropyridine (1.00 g, 5.19 mmol), (4-fluorophenyl)boronicacid (1.09 g, 7.79 mmol) and 2 M Na₂CO₃ solution (2 mL, 4 mmol) weredissolved in 10 mL of a mixture of toluene and EtOH and purged withargon for 30 min. Then Pd(PPh₃)₄ (300 mg, 0.25 mmol) was added and thereaction mixture was stirred for 12 h at 100° C. After cooling to RT,the reaction mixture was concentrated. Purification by silica gelchromatography (1-2% EtOAc in petroleum ether) provided2-chloro-6-(4-fluorophenyl)pyridine. m/z=184.1 [M+H]⁺, t_(R)=2.23 min(LCMS method a)

Step B:1-(4-chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

2-chloro-6-(4-fluorophenyl)pyridine (50 mg, 0.241 mmol),1-(4-chlorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (Intermediate C, 99mg, 0.27 mmol) and NaOtBu (35 mg, 0.36 mmol) were dissolved in 10 mL ofa mixture of toluene and EtOH and purged with argon for 30 min. ThenPd₂(dba)₃ (12 mg, 0.012 mmol) and Dave-phos (10 mg, 0.024 mmol) wereadded and the reaction mixture was stirred for 16 h at 100° C. Thereaction mixture was cooled to RT and concentrated. Purificaiton bypreparative HPLC provided the title compound (14 mg, 0.030 mmol) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.03 (dd, 2H), 7.55 (dd, 1H),7.42 (d, 2H), 7.25 (dd, 2H), 7.14 (d, 1H), 7.09 (d, 2H), 6.70 (d, 1H),4.25 (m, 2H), 2.95 (br t, 2H), 2.44 (t, 2H), 2.13 (m, 2H), 1.85-1.90 (m,4H), 1.57-1.64 (dt, 2H) ppm; m/z=450.2 [M+H]⁺; t_(R)=2.38 min (LCMSmethod d)

Example 33:2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine1-oxide

Step A: 4-bromo-2-chloropyridine 1-oxide

MCPBA (1.569 g, 9.09 mmol) was added portionwise to a solution of4-bromo-2-chloropyridine (0.50 g, 2.6 mmol) in DCM (24 mL). The reactionmixture was stirred overnight at 50° C., cooled to RT, diluted withEtOAc and washed with water, saturated aqueous sodium bisulfitesolution, and NaHCO₃ solution. The organic layer was dried over Na₂SO₄,filtered, and concentrated. Purification by silica gel chromatography(50-75% EtOAc in cyclohexane) followed by SFC (Reprosphere PEI 100 Å, 5μm, 30×250 mm; 2-7% MeOH in CO₂, 10 min) provided4-bromo-2-chloropyridine 1-oxide (78 mg, 0.37 mmol). ¹H NMR (400 MHz,DMSO-d₆) δ=8.36 (d, 1H), 8.19 (d, 1H), 7.66 (dd, 1H) ppm; m/z=208.0,210.0, 212.0 [M+H]⁺; t_(R)=0.45 min (LCMS method a)

Step B:4-bromo-2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)pyridine1-oxide

1-(4-Chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 111 mg, 0.374 mmol) and NaHCO₃ (29 mg, 0.34 mmol) wereadded to a solution of 4-bromo-2-chloropyridine 1-oxide (65 mg, 0.31mmol) in 1 mL of tert-amyl alcohol. The reaction mixture was refluxedovernight at 110° C. After cooling to RT the mixture was diluted withEtOAc and washed with water. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The crude product was purified bysilica gel chromatography (0-10% EtOAc in cyclohexane). ¹H NMR (400 MHz,DMSO-d₆) δ=7.99 (d, 1H), 7.65 (dd, 1H), 7.29 (d, 1H), 7.14-7.16 (m, 2H),7.01 (d, 1H), 3.76 (m, 2H), 2.84 (br t, 2H), 2.43 (t, 2H), 2.10-2.18 (m,2H), 1.8-1.9 (m, 4H), 1.7 (m, 2H) ppm; m/z=468.2, 470.2 [M+H]⁺;t_(R)=0.80 min (LCMS method a).

Step C:2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine1-oxide

K₃PO₄ (160 mg, 0.755 mmol) and PdCl₂(dtbpf) (16 mg, 0.025 mmol) wereadded to a solution of4-bromo-2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)pyridine1-oxide (118 mg, 0.250 mmol) and 4-fluorophenylboronic acid pinacolester (56 mg, 0.25 mmol) in 1.3 mL of dioxane and 0.43 mL of water. Thereaction mixture was heated under microwave irradiation for 45 min at110° C. After cooling to RT, the mixture was concentrated. Purificaitonby silica gel chromatography (0-7% MeOH in DCM) provided the titlecompound (52 mg, 0.11 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=8.12 (d, 1H),7.83 (d, 1H), 7.82 (d, 1H), 7.66 (t, 1H), 7.2-7.35 (m, 5H), 7.03 (d,1H), 3.84 (m, 2H), 2.87 (br t, 2H), 2.43 (t, 2H), 2.15 (m, 2H), 1.8-1.9(m, 4H), 1.7-1.8 (m, 2H) ppm; m/z=484.3 [M+H]⁺; t_(R)=0.92 min (LCMSmethod a).

Example 34:4-(3-chlorophenoxy)-2-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)pyridine1-oxide

The title compound was synthesized analogously to Example 33 startingwith 2-chloro-4-(3-chlorophenoxy)pyridine. ¹H NMR (300 MHz, DMSO-d6) δ8.02 (d, 1H), 7.56-7.41 (m, 2H), 7.35-7.21 (m, 3H), 7.07-7.10 (m, 1H),6.95-6.98 (m, 1H), 6.66 (d, 1H), 6.57 (dd, 1H), 3.83 (d, 2H), 2.77 (t,2H), 2.41 (t, 2H), 2.02-2.12 (m, 2H), 1.62-1.86 (m, 6H); m/z=500.2[M+H]⁺; t_(R)=1.34 min (LCMS method l)

Example 35a:9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

and

Example 35b:9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 2-chloro-4-(5-azaspiro[2.3]hexan-5-yl)pyrimidine and5-(4-chloropyrimidin-2-yl)-5-azaspiro[2.3]hexane

A mixture of 2,4-dichloropyrimidine (96 mg, 0.52 mmol),5-azaspiro[2.3]hexane (60 mg, 0.47 mmol) and triethylamine (65 μL, 0.47mmol) in DMF (1.5 mL) was stirred for 18 h at RT. Silica gelchromatography (ethyl acetate) provided a mixture of5-(2-chloropyrimidin-4-yl)-5-azaspiro[2.3]hexane and5-(4-chloropyrimidin-2-yl)-5-azaspiro[2.3]hexane which were useddirectly in the next step. m/z=195.9.

Step B:9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-oneand9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

The mixture 5-(2-chloropyrimidin-4-yl)-5-azaspiro[2.3]hexane and5-(4-chloropyrimidin-2-yl)-5-azaspiro[2.3]hexane from step A,1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate B, 111 mg, 0.375 mmol) and triethylamine (0.16 mL, 1.1mmol) in 1 mL of EtOH was stirred in a microwave oven for 1 h at 160° C.The reaction mixture was concentrated and the crude products werepurified by silica gel chromatography (0-15% MeOH in DCM) followed bypreparative HPLC (XBridge Phenyl OBD, 5 μm, 30×100 mm; mobile phase A:0.1% NH4OH, mobile phase B: ACN; 30 mL/min; 28-58% ACN over 15 min) toprovide the regioisomeric products:

Example 35a:9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.73 (d, J=6.36 Hz, 1H) 7.51 (t,J=8.38 Hz, 1H) 7.07 (dd, J=9.90, 2.20 Hz, 1H) 6.93 (dt, J=8.44, 1.04 Hz,1H) 6.01 (d, J=6.36 Hz, 1H) 4.30 (br d, J=12.35 Hz, 2H) 4.04 (s, 4H)3.01 (br t, J=12.41 Hz, 2H) 2.57 (t, J=6.79 Hz, 2H) 2.24 (br s, 2H)1.86-2.02 (m, 4H) 1.62-1.75 (m, 2H) 0.66 (s, 4H); m/z=456.2 [M+H]⁺;t_(R)=0.77 min (LCMS method a).

Example 35b:9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.73 (d, J=5.87 Hz, 1H) 7.49 (t,J=8.15 Hz, 1H) 7.06 (dd, J=9.90, 2.20 Hz, 1H) 6.91 (d, J=8.68 Hz, 1H)5.63 (d, J=5.99 Hz, 1H) 4.41-4.55 (m, 2H) 3.96-4.09 (m, 4H) 2.90-3.00(m, 2H) 2.57 (t, J=6.79 Hz, 2H) 2.16-2.28 (m, 2H) 1.81-2.04 (m, 4H) 1.67(td, J=12.65, 4.40 Hz, 2H) 0.63-0.71 (m, 4H); m/z=456.3 [M+H]⁺;t_(R)=0.81 min (LCMS method a).

By employing similar methods as described for the preparation ofExamples 35a and 35b using appropriate spirocyclic piperidineintermediates and commerically available amines for Step A, thefollowing compounds were prepared:

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 36

462.1; 1.12 min, LCMS method a ¹H NMR (400 MHz, DMSO-d₆) δ = 7.78 (d,1H), 7.6 (t, 1H), 7.23 (dd, 1H), 6.96 (dd, 1H), 3.95 (m, 2H), 3.5 (m,4H), 3.05 (m, 2H), 2.43 (t, 2H), 2.13 (m, 2H), 1.82 (m, 8H) 1.6 (m, 2H).ppm 37

516.2; 1.12 min, LCMS method a ¹H NMR (400 MHz, DMSO-d₆) δ = 7.82 (d,1H), 7.6 (t, 1H), 7.22 (dd, 1H), 6.96 (dd, 1H), 4.31 (m, 2H), 4.0-4.1(m, 4H), 3.7 (m, 1H), 3.08 (m, 2H), 2.43 (t, 2H), 2.13 (m, 2H), 1.82 (m,4H), 1.5-1.6 (m, 2H). ppm 38

445.2; 0.97 min, LCMS method a ¹H NMR (400 MHz, DMSO-d₆) δ = 8.01 (s,1H), 7.58 (t, 1H), 7.22 (d, 1H), 6.95 (d, 1H), 4.56 (m, 2H), 3.38 (m,4H), 2.94 (br t, 2H), 2.43 (t, 2H), 2.14 (m, 2H), 1.84-1.87 (m, 8H) 1.42(m, 2H) ppm 39

525.3; 0.48 min, LCMS method i ¹H NMR (400 MHz, DMSO- d6) δ 7.79 (d,1H), 7.41 (m, 1H), 7.30-7.15 (m, 1H), 6.91 (d, 1H), 6.05 (d, 1H), 4.47(d, 2H), 4.13 (brs, 2H), 3.12 (dt, 2H), 2.87 (t, 2H), 2.42 (t, 2H),2.05-2.11 (m, 4H), 1.79- 1.88 (m, 3H), 1.4-1.52 (m, 4H) ppm 40

527.4; 0.65 min, LCMS method i ¹H NMR (300 MHz, DMSO- d6) δ 8.06 (s,1H), 7.41 (m, 1H), 7.22 (m, 1H), 6.91 (d, 1H), 4.42-4.62 (m, 4H), 3.12-2.78 (m, 3H), 2.42 (t, 2H), 2.20-2.02 (m, 2H), 1.92- 1.79 (m, 4H),1.62-1.75 (m, 4H), 1.32-1.54 (m, 4H). 41

559.4; 0.58 min, LCMS method i ¹H NMR (300 MHz, DMSO- d6) δ 7.44 (m,1H), 7.23 (m, 1H), 6.91 (d, 1H), 5.99 (s, 1H), 5.70 (s, 2H), 3.82-4.0(m, 4H), 2.91-3.07 (m, 4H), 2.41 (t, 2H), 2.09 (m, 2H), 1.75-1.88 (m,4H), 1.51- 1.62 (m, 6H). 42

526.3; 1.28 min, LCMS method j ¹H NMR (chloroform-d, 300 MHz) δ 8.3 (s,1H), 7.25- 7.1 (m, 1H), 6.94-6.9 (m, 1H), 6.8 (m, 1H), 4.26-4.23 (m,2H), 3.70 (d, 2H), 3.25 (t, 2H), 2.99 (t, 2H), 2.62 (t, 2H), 2.1 (br,2H), 1.98-1.88 (m, 4H), 1.79-1.7 (m, 4H), 1.32- 1.25 (m, 2H). 43

459.3; 0.48 min, LCMS method i ¹H NMR (DMSO-d6, 300 MHz) δ 7.5-7.38 (m,1H), 7.3-7.18 (m, 1H), 6.92 (br, 1H), 5.63 (brs, 2H), 5.5 (s, 1H), 4.81(s, 1H), 4.09 (d, 2H), 3.64 (s, 4H), 2.79 (t, 2H), 2.41 (m, 2H), 2.08(br, 2H), 1.81-1.77 (m, 4H), 1.5- 1.35 (m, 4H) 44

516.1; 0.66 min, LCMS method i ¹H NMR (400 MHz, DMSO- d6) δ ppm 8.06 (s,1 H) 7.59 (t, J = 8.44 Hz, 1 H) 7.24 (dd, J = 10.27, 2.08 Hz, 1 H) 6.96(d, J = 8.65 Hz, 1 H) 5.70- 5.76 (m, 1 H) 4.25 (br d, J = 12.59 Hz, 2 H)4.09 (br t, J = 15.16 Hz, 4 H) 2.94 (br t, J = 12.47 Hz, 2 H) 2.39-2.47(m, 2 H) 1.93-2.19 (m, 2 H) 1.82-1.92 (m, 4 H) 1.48 (td, J = 12.84, 4.28Hz, 2 H) 45

458.4; 0.47 min, LCMS method i ¹H NMR (400 MHz, DMSO- d6) δ 7.97 (s,1H), 7.42 (dt, J = 10.9, 8.8 Hz, 1H), 7.31- 7.13 (m, 1H), 6.92 (dq, J =6.5, 2.3 Hz, 1H), 5.66 (s, 1H), 4.20 (d, J = 13.4 Hz, 2H), 3.64 (t, J =9.5 Hz, 6H), 3.57- 3.46 (m, 2H), 2.96-2.79 (m, 2H), 2.42 (t, J = 6.7 Hz,2H), 2.11 (s, 2H), 1.81 (td, J = 12.3, 5.6 Hz, 6H), 1.50 (dd, J = 14.4,9.9 Hz, 2H). 46

471.3; 0.44 min, LCMS method i 1H NMR (DMSO-d6, 300 MHz) δ 7.47-7.38 (m,1H), 7.28-7.2 (m, 1H), 6.94- 6.88 (m, 1H), 5.55 (br, 2H), 4.95 (br, 1H),4.73 (br, 1H), 4.57 (s, 1H), 4.12 (d, 2H), 3.7- 3.52 (m, 2H), 3.25 (s,1H), 3.17-3.09 (m, 1H), 2.78 (t, 2H), 2.41 (t, 2H), 2.07 (br, 2H),1.9-1.75 (m, 5H), 1.5- 1.38 (m, 2H).

Example 47:1-(3,4-difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A:(9-(6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 4,6-dichloropyrimidine (0.188 g, 1.26 mmol) and1-(3,4-difluorophenyl-1,9-diazaspiro[5.5]undecane-2-one hydrochloride(Intermediate A, 0.564, 1.26 mmol) in EtOH (2 mL) was treated with TEA(0.642 g, 1.50 mmol) and the reaction mixture was stirred at RT for 2 h.The mixture was concentrated and the residue partitioned between waterand EtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated to provide(9-(6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(0.410 g, crude) as a white solid. m/z=393.1 [M+H]⁺; t_(R)=1.43 min(LCMS method j)

Step B:1-(3,4-difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of(9-(6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(0.10 g, 0.25 mmol), 4-trifluoromethylpyrazole (0.041 g mmol, 0.30 mmol)and Cs₂CO₃ (0.165 g, 0.5 mmol) in DMF (1 mL) was heated at 120° C. for12 h. The mixture was cooled to RT, partitioned between water and EtOAc.The organic layer was dried over Na₂SO₄ and concentrated under reducedpressure. Purification by preparative HPLC (Waters Xbridge, 5 μm,21.2×150 mm; water/ACN elution) provided the title compound (24 mg,0.048 mmol) as an off-white solid. ¹H NMR (400 MHz, methanol-d₄) δ 8.92(s, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.24-7.31 (m, 1H), 7.16 (s, 1H),7.08-7.14 (m 1H), 6.92 (d, 1H), 4.40 (brs, 2H), 3.16 (t, 2H), 2.58 (t,2H), 2.27 (brs, 2H), 1.96-2.02 (m, 4H), 1.68-1.81 (m, 2H); m/z=493.2[M+H]⁺; t_(R)=1.25 min (LCMS method j)

By employing similar methods as described for the preparation of Example47, using appropriate starting materials, the following compounds wereprepared:

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 48

439.2; 1.53 min, LCMS method g ¹H NMR (400 MHz, DMSO- d6) δ 8.50 (s,1H), 7.80 (s, 1H), 7.42 (m, 1H), 7.25 (m, 1H), 6.91 (d, 1H), 6.87 (s,1H), 6.53 (s, 1H), 4.30 (brs, 2H), 3.06 (t, 3H), 2.40 (m, 3H), 2.15(brs, 2H), 1.8-1.95 (m, 4H), 1.53 (t, 2H). 49

450.2; 4.50 min, LCMS method f ¹H NMR (300 MHz, DMSO- d6) δ 8.52 (d,1H), 7.89 (s, 1H), 7.42 (m, 1H), 7.30-7.17 (m, 1H), 7.72 (s, 1H), 6.60(dd, 1H), 3.41 (m, 2H), 3.30-3.07 (brs, 2H), 2.45 (t, 2H), 2.12- 2.2 (m,2H), 1.8-1.98 (m, 4H), 1.5-1.62 9 (m, 2H)

Example 50:1-(3,4-difluorophenyl)-9-(2-methoxy-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 4-chloro-2-methoxy-6-(1H-pyrazol-1-yl)pyrimidine

A mixture of cesium carbonate (71.8 mg, 0.220 mmol), 1H-pyrazole (15 mg,0.22 mmol) and 4,6-dichloro-2-methoxypyrimidine (39 mg, 0.22 mmol) inDMF (0.9 mL) was stirred at RT for two hours. LCMS analysis indicatescomplete conversion to 4-chloro-2-methoxy-6-(1H-pyrazol-1-yl)pyrimidinewhich was not isolated. m/z=211.1 [M+H]⁺; t_(R)=0.93 min (LCMS method e)

Step B.1-(3,4-difluorophenyl)-9-(2-methoxy-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

To the reaction mixture in Step A was added1-(3,4-difluorophenyl-1,9-diazaspiro[5.5]undecane-2-one (Intermediate A,62 mg, 0.22 mmol), DIEA (0.13 mL, 0.74 mmol). The mixture was heated at50° C. overnight. After cooling to RT, the mixture was partitionedbetween 2:1 EtOAc/heptane, washed with water (5×), brine, dried oversodium sulfate and concentrated. Purification by silica gelchromatography (0-100% MeOH in EtOAc), followed by reverse phasechromatography (RediSep® Rf Gold® Reversed Phase C18 50 g column, 0-100%ACN in water) provided the title compound (30 mg, 0.065 mmol) as a whitesolid. ¹H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J=2.7, 0.7 Hz, 1H), 7.81(dd, J=1.6, 0.7 Hz, 1H), 7.42 (dt, J=10.7, 8.9 Hz, 1H), 7.25 (ddd,J=11.5, 7.4, 2.4 Hz, 1H), 6.93 (dtd, J=7.0, 2.5, 1.3 Hz, 1H), 6.73 (s,1H), 6.54 (dd, J=2.7, 1.6 Hz, 1H), 4.14 (d, J=100.0 Hz, 2H), 3.83 (s,3H), 3.09 (t, J=13.1 Hz, 2H), 2.44 (t, J=6.7 Hz, 2H), 2.15 (s, 2H),1.98-1.80 (m, 4H), 1.65-1.46 (m, 2H); m/z=455.3 [M+H]⁺; t_(R)=1.01 min(LCMS method e).

By employing similar methods as described for the preparation of Example50, using appropriate starting materials, the following compounds wereprepared:

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 51

493.2; 1.19 min, LCMS method e ¹H NMR (400 MHz, DMSO- d6) δ 8.50 (dd, J= 2.7, 0.7 Hz, 1H), 7.89 (dd, J = 1.6, 0.7 Hz, 1H), 7.42 (dt, J = 10.7,8.9 Hz, 1H), 7.25 (ddd, J = 11.6, 7.4, 2.4 Hz, 1H), 7.18 (s, 1H), 6.94(ddd, J = 8.7, 3.8, 1.8 Hz, 1H), 6.60 (dd, J = 2.7, 1.6 Hz, 1H),4.96-3.72 (m, 2H), 3.18 (s, 2H), 2.44 (t, J = 6.7 Hz, 2H), 2.16 (d, J =7.7 Hz, 2H), 2.01-1.91 (m, 2H), 1.86 (p, J = 6.6 Hz, 2H), 1.72- 1.50 (m,2H). 52

510.4; 1.08 min, LCMS method e ¹H NMR (400 MHz, DMSO- d6) δ 8.54 (dd, J= 2.6, 0.7 Hz, 1H), 7.75 (dd, J = 1.6, 0.7 Hz, 1H), 7.42 (dt, J = 10.6,8.9 Hz, 1H), 7.24 (ddd, J = 11.6, 7.4, 2.4 Hz, 1H), 6.93 (ddd, J = 9.6,4.5, 2.4 Hz, 1H), 6.49 (dd, J = 2.6, 1.6 Hz, 1H), 6.43 (s, 1H), 4.23 (s,2H), 3.71-3.58 (m, 8H), 3.02 (t, J = 13.1 Hz, 2H), 2.43 (t, J = 6.7 Hz,2H), 2.13 (s, 2H), 1.99-1.75 (m, 4H), 1.62- 1.45 (m, 2H). 53

468.4; 1.18 min, LCMS method e ¹H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J =2.6, 0.8 Hz, 1H), 7.74 (dd, J = 1.6, 0.7 Hz, 1H), 7.42 (dt, J = 10.7,8.9 Hz, 1H), 7.24 (ddd, J = 11.6, 7.4, 2.4 Hz, 1H), 6.99-6.88 (m, 1H),6.49 (dd, J = 2.6, 1.6 Hz, 1H), 6.37 (s, 1H), 4.24 (s, 2H), 3.07 (s,6H), 3.00 (d, J = 13.1 Hz, 2H), 2.43 (t, J = 6.7 Hz, 2H), 2.14 (s, 2H),1.96-1.75 (m, 4H), 1.54 (d, J = 13.8 Hz, 2H). 54

426.2; 0.80 min, LCMS method e ¹H NMR (400 MHz, DMSO- d6) δ 9.31 (s,1H), 8.43 (d, J = 0.9 Hz, 1H), 8.31 (s, 1H), 7.42 (dt, J = 10.7, 8.9 Hz,1H), 7.25 (ddd, J = 11.6, 7.5, 2.5 Hz, 1H), 7.00 (d, J = 1.1 Hz, 1H),6.93 (ddt, J = 8.6, 3.9, 1.9 Hz, 1H), 4.09 (d, J = 5.3 Hz, 2H), 3.12 (t,J = 13.2 Hz, 2H), 2.44 (t, J = 6.7 Hz, 2H), 2.16 (s, 2H), 2.00-1.78 (m,4H), 1.67-1.46 (m, 2H). 55

459.2; 1.15 min, LCMS method e ¹H NMR (400 MHz, DMSO- d6) δ 8.71 (d, J =0.8 Hz, 1H), 8.38 (d, J = 0.9 Hz, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.41(dt, J = 10.7, 8.9 Hz, 1H), 7.24 (ddd, J = 11.6, 7.5, 2.5 Hz, 1H), 7.01(d, J = 1.0 Hz, 1H), 6.97-6.85 (m, 1H), 3.38 (s, 2H), 3.10 (t, J = 13.1Hz, 2H), 2.43 (t, J = 6.7 Hz, 2H), 2.15 (s, 2H), 2.00-1.75 (m, 4H), 1.55(td, J = 12.9, 4.7 Hz, 2H). 56

443.2; 1.06 min, LCMS method e ¹H NMR (400 MHz, DMSO- d6) δ 8.60 (dd, J= 4.5, 0.9 Hz, 1H), 8.37 (d, J = 0.9 Hz, 1H), 7.96 (dd, J = 4.3, 0.9 Hz,1H), 7.41 (dt, J = 10.7, 8.9 Hz, 1H), 7.24 (ddd, J = 11.6, 7.5, 2.5 Hz,1H), 7.01 (d, J = 1.0 Hz, 1H), 6.93 (ddt, J = 8.7, 3.8, 1.6 Hz, 1H),4.30 (s, 2H), 3.10 (t, J = 13.1 Hz, 2H), 2.43 (t, J = 6.8 Hz, 2H), 2.15(s, 2H), 1.97-1.75 (m, 4H), 1.55 (td, J = 13.1, 12.4, 4.3 Hz, 2H). 57

493.1; 1.60 min, LCMS method f ¹H NMR (400 MHz, methanol- d₄) δ8.65-8.64 (m, 1H), 8.37 (s, 1H), 7.32-7.25 (m, 1H), 7.14-7.08 (m, 2H),6.93- 6.91 (m, 1H), 6.82 (m, 1H), 4.45 (brs, 2H), 3.16 (t, 2H), 2.58 (t,2H), 2.27 (br, 2H), 2.03-1.96 (m, 4H), 1.82- 1.7 (m, 2H). 58

492.9; 0.65 min, LCMS method i ¹H NMR (400 MHz, chloroform-d) δ 8.44 (s,1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.21-7.12 (m, 1H), 6.92- 6.86 (m, 1H),6.82-6.74 (m, 1H), 6.35 (s, 1H), 4.45 (brs, 2H), 3.1 (t, 2H), 2.64-2.62(m, 2H), 2.2-2.17 (m, 2H), 1.99-1.81 (m, 6H). 59

458.3; 0.58 min, LCMS method i 1H NMR (DMSO-d6, 300 MHz) δ 8.21 (d, 1H),7.76 (s, 1H), 7.5-7.39 (m, 1H), 7.3- 7.2 (m, 1H), 6.96-6.9 (m, 1H),6.5-6.49 (m, 1H), 6.32 (s, 2H), 4.2 (d, 2H), 3.12 (t, 2H), 2.42 (t, 2H),2.2-2.1 (m, 2H), 1.89-1.84 (m, 4H), 1.68- 1.52 (m, 2H). 60

459.3; 0.65 min, LCMS method l ¹H NMR (chloroform-d, 300 MHz) δ 8.25 (d,1H), 7.63 (d, 1H), 7.2-7.12 (m, 1H), 6.9- 6.84 (m, 1H), 6.8-6.72 (m,1H), 5.3 (br, 2H), 4.8 (br, 2H), 3.05-2.9 (m, 2H), 2.62 (t, 2H),2.2-2.12 (br, 2H), 1.97- 1.92 (m, 2H), 1.81-1.7 (m, 4H). 61

499.3; 1.11 min, LCMS method e ¹H NMR (400 MHz, methanol- d₄) δ 7.29(dt, J = 10.5, 8.8 Hz, 1H), 7.16-7.05 (m, 1H), 6.92 (ddt, J = 8.3, 3.9,2.0 Hz, 1H), 6.11 (s, 1H), 5.57 (p, J = 5.7 Hz, 1H), 4.92 (t, J = 6.9Hz, 2H), 4.63 (dd, J = 7.6, 5.1 Hz, 2H), 4.29 (s, 2H), 3.10 (td, J =13.3, 2.8 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H), 2.35-2.16 (m, 2H), 1.97(td, J = 13.3, 7.6 Hz, 4H), 1.73 (s, 2H).

Example 62:1-(3,4-difluorophenyl)-9-(6-(oxazol-2-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of9-(6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(0.15 g, 0.38 mmol) in DMF (2 mL) was purged with argon gas and treatedwith 2-(tributylstannyl)oxazole (0.273 g, 0.76 mmol) and tetrakistriphenylphosphine palladium(0) (0.080 g, 0.11 mmol). The reactionmixture was heated to 100° C. for 16 h. The reaction mixture was cooledto RT, diluted with water, and extracted with EtOAc twice. The combinedorganic extracts were washed with brine, dried over anhydrous Na₂SO₄,and concentrated under reduced pressure. Purification by preparativeHPLC (LUNA 5.0μ, 21.2×250 mm; 0.1% aqueous HCOOH:ACN elution) providedthe title compound (44 mg) as an off-white solid. ¹H NMR (chloroform-d,600 MHz) δ 8.64 (s, 1H), 7.81 (s, 1H), 7.29 (m, 1H), 7.25-7.24 (m, 1H),7.25-7.14 (m, 1H), 6.89-6.88 (m, 1H), 6.78-6.77 (m, 1H), 4.41 (brs, 2H),3.1 (t, 2H), 2.63-2.62 (m, 2H), 2.17 (m, 2H), 2.00-1.94 (m, 2H),1.87-1.78 (m, 4H); m/z=426.2 [M+H]⁺; t_(R)=1.33 min (LCMS method j).

Example 63:9-(6-amino-2-(pyridin-2-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 6-chloro-2-(pyridin-2-yl)pyrimidin-4-amine

A suspension of 4,6-dichloro-2-(pyridin-2-yl)pyrimidine (112 mg, 0.495mmol) in isopropanol (0.5 mL) and ammonium hydroxide (33%, 0.5 mL, 4.24mmol) was stirred at 50° C. After 3 h, an additional portion of ammoniumhydroxide solution (0.25 mL) as added and stirring continued for 3 h.The solution was cooled to RT, diluted with saturated sodium bicarbonateand extracted with DCM. The organic extracts were dried over magnesiumsulfate and concentrated to provide6-chloro-2-(pyridin-2-yl)pyrimidin-4-amine (85 mg, 0.41 mmol) as atan-colored solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.68 (ddd, J=4.7, 1.8,0.9 Hz, 1H), 8.21 (dt, J=8.0, 1.1 Hz, 1H), 7.93 (td, J=7.7, 1.8 Hz, 1H),7.50 (ddd, J=7.5, 4.7, 1.2 Hz, 1H), 7.40 (s, 2H), 6.48 (s, 1H);m/z=207.1 [M+H]⁺; t_(R)=0.48 min (LCMS method e).

Step B:9-(6-amino-2-(pyridin-2-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate A, 56 mg, 0.20 mmol),6-chloro-2-(pyridin-2-yl)pyrimidin-4-amine (41 mg, 0.20 mmol) and DIEA(104 μL, 0.595 mmol) in DMF (0.7 mL) was heated at 100° C. overnight.After cooling to RT, the mixture was diluted with DCM and washed withwater, then brine. The organic layer was dried over magnesium sulfate,filtered and concentrated. Purification by silica gel chromatography(0-100% MeOH in EtOAc), followed by reverse phase chromatography(RediSep® Rf Gold® Reversed Phase C18 50 g column, 0-100% ACN in water)provided the title compound (16 mg, 0.034 mmol) as a white solid. ¹H NMR(400 MHz, DMSO-d6) δ 8.61 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.23-8.08 (m,1H), 7.83 (td, J=7.7, 1.8 Hz, 1H), 7.51-7.34 (m, 2H), 7.25 (ddd, J=11.5,7.5, 2.4 Hz, 1H), 7.00-6.88 (m, 1H), 6.32 (s, 2H), 5.56 (s, 1H), 4.18(s, 2H), 2.95 (t, J=12.9 Hz, 2H), 2.43 (t, J=6.8 Hz, 2H), 2.13 (s, 2H),1.88 (t, J=9.5 Hz, 4H), 1.55 (t, J=11.1 Hz, 2H); m/z=451.3 [M+H]⁺;t_(R)=1.29 min (LCMS method e).

Example 64:9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

Step A: 4-Chloro-6-(4-trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-amine

A mixture of 4-(trifuoromethyl)-1H-pyrazole (0.183 g, 1.35 mmol),2-amino-4,6-dichloropyrimidine (0.200 g, 1.23 mmol) and Cs₂CO₃ (0.799 g,2.45 mmol) in dioxane (4 mL) were stirred at 100° C. for 12 h. Aftercooling to RT, the reaction mixture was diluted with water and extractedwith EtOAc. The extracts were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to provide4-chloro-6-(4-trifluoromethyl)-1H pyrazol-1-yl)pyrimidin-2-amine as awhite solid. The crude was taken for the next step without purification.m/z=264.0 [M+H]⁺

Step B:9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one (IntermediateA, 0.150 g, 0.535 mmol), 4-chloro-6-(4-trifluoromethyl)-1Hpyrazol-1-yl)pyrimidin-2-amine (0.197 g, 0.749 mmol) and DIPEA (0.28 mL,1.61 mmol) in EtOH (3 mL) were stirred at 80° C. for 12 h. The reactionwas diluted with water and extracted with EtOAc. The extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. Purification by preparative HPLC (KINETEX EVO C18, 5μm, 21.2×150 mm; water:ACN elution) provided the title compound (97 mg,0.19 mmol) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H),8.21 (s, 1H), 7.41 (m, 1H), 7.23 (m, 1H), 6.91 (m, 1H), 6.41 (d, 3H),4.24 (m, 2H), 3.01 (t, 2H), 2.42 (t, 2H), 2.13 (d, 2H), 1.85 (m, 4H),1.50 (m, 2H); m/z=508.15 [M+H]⁺; t_(R)=1.50 min (LCMS method j)

Example 65:1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one

Step A: methyl4-chloro-6-(4-trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate

A mixture of methyl 4,6-dichloropyrimidine-2-carboxylate (0.500 g, 2.66mmol), 4-(trifluoromethyl)-1H-pyrazole (0.360 g, 2.66 mmol) and Cs₂CO₃(1.70 g, 5.31 mmol) in dioxane (5 mL) was stirred at RT for three hours.Water was added to the reaction mixture and it was extracted with EtOAc.The extracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide methyl4-chloro-6-(4-trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylateas a white solid (0.550 g). The crude was taken on without furtherpurification.

Step B: methyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(4-chloro-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate A, 0.370 g, 1.35 mmol),methyl-4-chloro-6-(4-trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate(0.550 g, 1.79 mmol) and DIPEA (0.700 g, 5.37 mmol) in EtOH (5 mL) wereheated at 80° C. for two hours. The mixture was diluted with water andextracted with EtOAc twice. The extracts were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure toprovide methyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(4-chloro-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate(0.350 g, 0.636 mmol) as a white solid. m/z=551.2 [M+H]⁺

Step C:1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one

Methylmagnesium bromide (3.0 M solution in diethyl ether, 0.034 mL, 0.10mmol) was added to a stirred solution of methyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(4-chloro-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate(0.050 g, 0.034 mmol) in THF (2 mL) cooled to 0° C. The reaction mixturewas then stirred at RT for three hours. The reaction was quenched withaqueous NH₄Cl and extracted with EtOAc. The extracts were washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purificaiton by preparative HPLC (LUNA Phenomenex, 5 μm,21.2×250 mm; 0.02% NH₄OH in H₂O:ACN elution) provided the title compound(3 mg, 0.006 mmol) as a white solid. ¹H NMR (300 MHz, methanol-d₄) b9.16 (s, 1H), 8.02 (s, 1H), 7.23-7.28 (m, 1H), 7.07-7.14 (m, 1H), 7.04(s, 1H), 6.90-6.94 (m, 1H), 4.45 (brs, 2H), 3.16 (t, 2H), 2.58 (t, 2H),2.19-2.35 (m, 2H), 1.88-2.09 (m, 4H), 1.76 (brs, 2H), 1.51 (s, 6H);m/z=551.2 [M+H]⁺; t_(R)=1.80 min (LCMS method l).

Example 66: Synthesis1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one

Step A:1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one

To a stirred solution of methyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(4-chloro-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate(1.100 g, 1.998 mmol) in MeOH (15 mL) cooled to 0° C., NaBH₄ (0.230 g,5.99 mmol) was added portionwise. The reaction mixture was stirred at RTfor two hours. The reaction was quenched with water and extracted withEtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. Washing the resulting solidwith pentane provided the title compound (0.950 g, 1.82 mmol) as anoff-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.30 (s, 1H),7.42 (m, 1H), 7.25 (m, 1H), 6.9-6.96 (m, 2H), 4.97 (t, 1H), 4.37 (d,2H), 3.10-3.18 (m, 2H), 2.40-2.45 (m, 2H), 2.1-2.2 (m, 2H), 1.8-1.98 (m,4H), 1.49-1.6 (m, 2H) (2 aliphatic protons merged with DMSO peak);m/z=523.2 [M+H]⁺; t_(R)=1.64 min (LCMS method l)

Example 67:rac-1-(3,4-difluorophenyl)-9-(2-(1-hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one

Step A:4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carbaldehyde(1p)

MnO₂ (0.230 g, 2.6 mmol) was added to a stirred solution of1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one(0.020 g, 0.038 mmol) in DCM (5 mL) cooled to 0° C. The reaction mixturewas stirred at RT for 12 h. The reaction mixture was poured into waterand extracted with EtOAc. The extracts were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure toprovide crude product as yellow gummy solid (0.025 g) which was takenforward without purification. m/z=523.2 [M+H]⁺

Step B:rac-1-(3,4-difluorophenyl)-9-(2-(1-hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyraol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one

MeMgBr (3.0 M in diethylether, 170 μL, 0.52 mmol) was added to a stirredsolution of4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carbaldehyde(0.080 g, 0.172 mmol) in THF (2 mL) cooled to 0° C. The reaction mixturewas stirred at RT for 3 hours. The reaction was quenched with aqueousNH₄Cl and extracted with EtOAc. The extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by preparative HPLC (LUNA Phenomenex, 5 μm, 21.2×250 mm;0.02% NH₄OH in H₂O:ACN elution) provided the title compound (2 mg, 0.004mmol) as an off-white solid. ¹H NMR (300 MHz, methanol-d₄) δ 9.13 (s,1H), 8.02 (s, 1H), 7.28 (m, 1H), 7.11 (m, 1H), 7.04 (s, 1H), 6.92 (m,1H), 4.65 (q, 1H), 4.46 (s, 2H), 3.15 (m, 2H), 2.58 (t, 2H), 2.27 (d,2H), 1.98 (dd, 4H), 1.75 (s, 2H), 1.46 (d, 3H); m/z=537.3 [M+H]⁺;t_(R)=1.74 min (LCMS method l).

Example 68:4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carboxamide

Step A:4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carboxamide

Ammonia (2.0 M in ethanol, 3 mL) was added to methyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(4-chloro-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate(0.085 g, 0.15 mmol) and the mixture heated at 50° C. for 4 hours. Themixture was concentrated under reduced pressure. Purification bypreparative HPLC (Waters Xbridge, 5 μm, 21.2×150 mm; 0.02% NH₃ inH₂O:ACN elution) provided the title compound (0.028 g, 0.052 mmol) as anoff-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H), 8.50 (s, 1H),8.32 (s, 1H), 7.74 (s, 1H), 7.41 (m, 1H), 7.2-7.3 (m, 1H), 7.13 (s, 1H),6.9-6.94 (m, 1H), 3.14 (s, 2H), 2.44 (t, 3H), 2.17 (m, 2H), 2.00-1.86(m, 4H), 1.56 (t, 2H); m/z=536.4 [M+H]⁺; t_(R)=1.47 min (LCMS method l)

Example 69:9-(2-chloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step-A: 2,4-dichloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine

A mixture of 2,4,6-trichloropyrimidine (0.50 g, 2.7 mmol),4-(trifluoromethyl)-1H-pyrazole (0.27 g, 2.0 mmol) and Cs₂CO₃ (1.70 g,5.45 mmol) in dioxane (5 mL) was stirred at RT for 3 h. The reactionmixture was diluted with water and extracted with EtOAc twice. Theextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to provide the crude product (0.20g) which was used for next step without further purification.

Step-B:9-(2-chloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of2,4-dichloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (0.20 g,0.71 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate A, 0.197 g, 0.706 mmol) and DIPEA (0.27 mL, 2.1 mmol) inEtOH (3 mL) was heated at 80° C. for 2 h. The reaction mixture wascooled to RT, diluted with water and extracted with EtOAc twice. Thecombined extracts were washed with brine, dried over Na₂SO₄, filteredand concentrated under reduced pressure. Purification by preparativeHPLC (YMC-ACTUS TRIART, 5.0 μm, 20×150 mm; 0.02% NH₄OH in water:ACNelution) provided the title compound (85 mg, 0.16 mmol). ¹H NMR (300MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.20 (s, 1H), 7.41 (m, 1H), 7.25 (m, 1H),6.99-6.83 (m, 2H), 4.82 (s, 1H), 3.96 (s, 1H), 3.10 (brs, 2H), 2.42 (t,2H), 2.14 (d, 2H), 2.01-1.72 (m, 4H), 1.53 (m, 2H); m/z=527.1 [M+H]⁺;t_(R)=1.74 min (LCMS method l).

By employing similar methods as described for the preparation of Example69, using appropriate starting materials, the following compounds wereprepared:

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 70

479.2; 1.47 min, LCMS method j ¹H NMR (400 MHz, DMSO-d₆) δ 7.43 (m, 1H),7.25 (m, 1H), 6.92 (m, 1H), 6.54 (s, 1H), 5.32 (t, 1H), 3.66- 3.86 (m,4H), 3.03 (t, 2H), 3.21-3.13 (m, 1H), 2.42 (t, 2H), 2.25-2.02 (m, 3H),1.71- 1.98 (m, 5H), 1.46-1.52 (m, 2H) 71

479.2; 1.47 min, LCMS method j ¹H NMR (DMSO-d₆, 300 MHz) δ 7.46-7.38 (m,1H), 7.24- 7.2 (m, 1H), 6.84 (m, 1H), 6.62 (s, 1H), 6.32-5.28 (m, 1H),4.5-3.62 (m, 6H), 3.0 (br, 2H), 2.42-2.39 (m, 2H), 2.18-2.07 (m, 3H),1.92- 1.74 (m, 5H), 1.52-1.4 (m, 2H). 72

479.4; 1.74 min, LCMS method l ¹H NMR (DMSO-d₆, 300 MHz) δ 7.44-7.3 (m,1H), 7.24- 7.18 (m, 1H), 6.92-6.88 (m, 1H), 6.08 (s, 1H), 5.4 (m, 1H),4.42-4.32 (m, 2H), 3.88- 3.62 (m, 4H), 3.0 (t, 2H), 2.42- 2.40 (m, 3H),2.25-2.08 (m, 3H), 1.88-1.84 (m, 4H), 1.51-1.4 (m, 2H).

Example 73:1-(3,4-difluorophenyl)-9-(6-(4-fluoro-1H-pyrazol-1-yl)-2-morpholinopyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 2,4-dichloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidine

A mixture of 2,4,6-trichloropyrimidine (0.200 g, 1.09 mmol), Cs₂CO₃(1.42 g, 2.18 mmol) and 4-fluoro-1H-pyrazole (0.18 g, 2.2 mmol) indioxane (6 mL) was stirred at RT for 12 h. The reaction mixture wasdiluted with water and extracted with EtOAc twice. The extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. Purification by preparative TLC eluting with 1:1EtOAc/hexane provided2,4-dichloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidine as an off-whitesolid (60 mg, 0.26 mmol); m/z=233.0, [M+H]⁺

Step B:9-(2-chloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 2,4-dichloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidine (60mg, 0.26 mmol) in EtOH (5 mL) was treated with1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (Intermediate A,72 mg, 0.26 mmol) and DIPEA (0.10 mL, 0.77 mmol), and heated at 80° C.for 2 h. The reaction mixture was cooled to RT, diluted with water, andextracted with EtOAc twice. The extracts were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude solid was washed with pentane to provide9-(2-chloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(110 mg, 0.231 mmol) as an off-white solid. m/z=476.9 [M+H]⁺

Step-C:1-(3,4-difluorophenyl)-9-(6-(4-fluoro-1H-pyrazol-1-yl)-2-morpholinopyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of9-(2-chloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(100 mg, 0.209 mmol) in n-butanol (2 mL) was treated with morpholine (91mg, 1.0 mmol) and DIPEA (80 μL, 0.45 mmol) and the reaction mixture washeated at 120° C. for 12 h. The reaction mixture was cooled to RT,diluted with water, and extracted with EtOAc twice. The extracts werewashed with brine solution, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude solid was washed withpentane to afford the title compound (34 mg, 0.064 mmol) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (dd, 1H), 7.76 (dd, 1H),7.39-7.45 (m, 1H), 7.1-7.26 (m, 1H), 6.92-6.94 (m, 1H), 5.76 (s, 1H),4.33 (brs, 2H), 3.63 (m, 4H), 3.53 (m, 4H), 2.96 (t, 2H), 2.43 (t, 2H),2.14 (brs, 2H), 1.95-1.78 (m, 3H), 1.50 (m, 2H); m/z=528.3 [M+H]⁺;t_(R)=1.37 min (LCMS method k).

Example 74:9-(2-amino-6-(4,4-difluorocyclohex-1-en-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A:9-(2-amino-6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate A, 0.513 g, 1.83 mmol), 2-amino-4,6-dichloropyrimidine(0.300 g, 1.83 mmol) and DIPEA (0.64 mL, 3.7 mmol) in EtOH (7 mL) washeated at 80° C. for 12 hours. After cooling to RT, the mixture wasdiluted with water and extracted with EtOAc. The extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purification by silica gel chromatography (2-5% MeOH in DCM)provided9-(2-amino-6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(0.520 g, 1.27 mmol) as a white solid. m/z=410.3 [M+2]

Step B:9-(2-amino-6-(4,4-difuorocyclohex-1-en-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

9-(2-amino-6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(0.300 g, 0.735 mmol) and2-(4,4-difluorocyclohex-1-en-1-yl))-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.540 g, 2.21 mmol) were stirred in DME (6 mL) and H₂O (2 mL) at RTwith argon purging for 10 min. K₂CO₃ (0.304 g, 2.21 mmol) was added tothe reaction mixture under argon purging followed by the addition ofPd(dppf)Cl₂-DCM (0.120 g, 0.147 mmol). The mixture was heated at 100° C.for 16 h. After cooling to RT, water was added to the reaction mixtureand it was extracted with EtOAc. The extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by preparative HPLC (Waters Xbridge, 5 μm, 21.2×150 mm;0.02% NH₄OH in H₂O:ACN elution) provided the title compound (17 mg,0.035 mmol) as a white solid. ¹H NMR (300 MHz, chloroform-d) δ 7.17 (m,1H), 6.72-6.92 (m, 2H), 6.53 (s, 1H), 5.88 (s, 1H), 4.68 (s, 2H), 4.26(d, 2H), 3.53 (brs, 2H), 2.90-2.96 (m, 2H), 2.59-2.81 (m, 6H), 2.1-2.22(m, 2H), 1.92-1.96 (m, 2H), 1.74-1.92 (m, 2H); m/z=490.25 [M+H]⁺;t_(R)=1.32 min (LCMS method j)

Example 75:9-(2-amino-6-(4-fluorophenyl-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

9-(2-amino-6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(0.100 g, 0.245 mmol) and 4-fluorophenylboronic acid (0.068 g, 0.49mmol) were stirred in DME (0.9 mL) and H₂O (2.1 mL) at RT with argonpurging for 10 min. K₂CO₃ (0.101 g, 0.735 mmol) was added to thereaction mixture under argon purging followed by the addition ofPd(dppf)Cl₂-DCM (0.035 g, 0.049 mmol). The mixture was heated at 90° C.for 16 h. After cooling to RT, water was added to the reaction mixtureand it was extracted with EtOAc. The extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by preparative HPLC (Gemini, 5 μm, 21.2×250 mm; 0.02% NH₄OHin H₂O:ACN elution) provided the title compound (50 mg, 0.11 mmol) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (m, 2H), 7.36-7.48 (m,1H), 7.21-7.35 (m, 3H), 6.9-6.94 (m, 1H), 6.92-6.49 (s, 1H), 6.05 (s,2H), 4.3-4.62 (m, 2H), 2.93 (t, 2H), 2.41-2.43 (m, 2H), 2.07-2.15 (m,2H), 1.79-1.93 (m, 4H), 1.57-1.35 (m, 2H); m/z=468.25 [M+H]⁺; t_(R)=1.30min (LCMS method j)

Example 76:9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate A, 50 mg, 0.18 mmol),4-chloro-6-(trifluoromethyl)pyrimidin-2-amine (49 mg, 0.25 mmol) andcesium carbonate (106 mg, 0.325 mmol) in DMF (0.7 mL) was heated at 50°C. for three hours. The reaction was cooled to RT, diluted with water,extracted with DCM, dried over magnesium sulfate and concentrated.Purification by reverse phase chromatography (RediSep® Rf Gold® ReversedPhase C18 50 g column, 0-100% ACN in water) provided the title compound(55 mg, 0.125 mmol) as a white solid. 1H NMR (400 MHz) δ 7.38-7.22 (m,1H), 7.17-7.03 (m, 1H), 6.98-6.85 (m, 1H), 6.65 (s, 1H), 4.43 (s, 2H),3.20 (t, J=13.6 Hz, 2H), 2.58 (t, J=6.9 Hz, 2H), 2.26 (d, J=7.8 Hz, 2H),2.10-1.89 (m, 4H), 1.75 (s, 2H); m/z=242.3 [M+H]⁺; t_(R)=0.88 min (LCMSmethod h)

Example 77:9-(2-amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

Step A: 2-amino-6-(perfluoroethyl)pyrimidine-4-ol

A mixture of ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (3.00 g, 12.8mmol), guanidine hydrochloride (3.65 g, 38.4 mmol) and NaOMe (1.30 g,24.0 mmol) in MeOH (10 mL) were stirred at 80° C. for 12 h. Water wasadded to the reaction mixture and it was extracted with EtOAc. Theextracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide2-amino-6-(perfluoroethyl)pyrimidine-4-ol as gummy brown mass (2.645 g).The crude product was taken further without purification. m/z=230.2[M+H]⁺

Step B: 4-chloro-6-(perfluoroethyl)pyrimidine-2-amine

A mixture of POCl₃ (39 mL, 30 v) and2-amino-6-(perfluoroethyl)pyrimidine-4-ol (1.30 g, 5.67 mmol) wasrefluxed at 100° C. for 12 h. After cooling to RT, aqueous NaHCO₃ wasadded and the mixture extracted with EtOAc. The extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purification by silica gel chromatography (8-12% EtOAc inhexane) provided 4-chloro-6-(perfluoroethyl)pyrimidine-2-amine (0.180 g,0.728 mmol) as a yellow liquid. m/z=248.1 [M+H]⁺

Step C:9-(2-amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

A mixture of 4-chloro-6-(perfluoroethyl)pyrimidine-2-amine (0.180 g,0.725 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate A, 0.163 g, 0.581 mmol) and DIPEA (0.38 mL, 2.2 mmol) inEtOH (5 mL) were stirred at 80° C. for 12 h. Water was added to thereaction mixture and it was extracted with EtOAc. The extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. Purification by preparative HPLC (Waters Xbridge, 5μm, 20×150 mm; 0.02% NH₄OH in H₂O: ACN elution) provided the titlecompound (16 mg, 0.033 mmol) as a white solid. ¹H NMR (300 MHz, DMSO-d₆)δ 7.42 (m, 1H), 7.24 (m, 1H), 6.97-6.84 (m, 1H), 6.55 (s, 2H), 6.33 (s,1H), 2.97 (m, 2H), 2.42 (t, 4H), 2.12 (m, 2H), 1.86 (d, 4H), 1.49 (m,2H); m/z=492.4 [M+H]⁺; t_(R)=2.12 min (LCMS method l)

Example 78:9-(2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: ethyl 4,4,5,5-tetrafluoro-3-oxopentanoate

NaH (1.125 g, 46.88 mmol) was added to a stirred solution of methyl2,2,3,3-tetrafluoropropanoate (2.50 g, 15.6 mmol) in EtOAc (10 mL). Thereaction mixture was refluxed at 70° C. for 12 hours. Water was added tothe reaction mixture and it was extracted with EtOAc. The extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure to provide the crude product as yellow liquid (4.361g). The crude was taken on to the next step without purification.m/z=215.1 [M+H]⁺

Step B: 2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-ol

A mixture of ethyl 4,4,5,5-tetrafluoro-3-oxopentanoate (2.00 g, 9.24mmol), guanidine hydrochloride (2.638 g, 27.77 mmol) and NaOMe (0.749 g,13.9 mmol) in MeOH (20 mL) were stirred at 80° C. for 12 h. Water wasadded to the reaction mixture and it was extracted with EtOAc. Theextracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Washing the resulting solids withpentane and EtOAc provided2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-ol (0.728 g, 3.45 mmol)as a yellow solid. m/z=212.05 [M+H]⁺

Step C:9-(2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-ol (0.200g, 0.947 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate A, 0.265 g, 0.947 mmol), PyBrop (0.485 g, 1.04 mmol) andTEA (0.40 mL, 2.8 mmol) in MeCN (4 mL) were heated at 80° C. for 24 h.Water was added to the reaction mixture and it was extracted with EtOAc.The extracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification by silica gelchromatography (EtOAc elution) provided the title compound as a paleyellow solid (0.231 g, 0.489 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (m,1H), 7.23 (m, 1H), 6.90-6.92 (m, 1H), 6.42-6.7 (m, 3H), 6.27 (s, 1H),4.25 (brs, 2H), 2.97 (t, 2H), 2.42 (t, 2H), 2.19-2.05 (m, 2H), 1.93-1.75(m, 4H), 1.58-1.38 (m, 2H); m/z=474.2 [M+H]⁺; t_(R)=1.28 min (LCMSmethod j)

Example 79:1-(3,4-difluorophenyl)-9-(2-(hydroxynethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecane-2-one

Step A: 2-(Chloromethyl)-6-(perfluoroethyl)pyrimidine-4-ol

A mixture of ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (5.0 g, 21mmol), 2-chloroacetimidamide hydrochloride (5.89 g, 45.7 mmol) and NaOMe(1.73 g, 32.0 mmol) in MeOH (20 mL) were stirred at 80° C. for 12 h.Water was added to the reaction mixture and it was extracted with EtOAc.The extracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purfication by silica gelchromatography (35-40% EtOAc in hexane) provided2-(chloromethyl)-6-(perfluoroethyl)pyrimidine-4-ol as an orange solid(0.254 g, 0.977 mmol). m/z=260.95, [M+H]⁺

Step B:9-(2-(chloromethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one

A mixture of 2-(chloromethyl)-6-(perfluoroethyl)pyrimidine-4-ol (0.100g, 0.381 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate A, 0.106 g, 0.381 mmol), PyBrop (0.266 g, 0.571 mmol) andTEA (0.16 mL, 1.1 mmol) in dioxane (5 mL) was stirred at RT for 12 h.Water was added to the reaction mixture and it was extracted with EtOAc.The extracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification by preparative TLC byeluting with EtOAc provided9-(2-(chloromethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-oneas a yellow solid (0.091 g, 1.91 mmol). m/z=525.1 [M+H]⁺

Step C:(4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(perfluoroethyl)pyrimidin-2-yl)methylacetate

KOAc (0.044 g, 0.458 mmol) was added to a stirred solution of9-(2-(chloromethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(0.080 g, 0.152 mmol) in DMF (4 mL). The reaction mixture was allowed tostir at RT for 12 h. Cold water was added to the reaction mixture and itwas extracted with EtOAc. The extracts were washed with brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure toprovide(4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(perfluoroethyl)pyrimidin-2-yl)methylacetate(0.045 g, 0.082 mmol) as a sticky yellow solid which was taken to thenext step without purification. m/z=549.1 [M+H]⁺; t_(R)=1.55 min (LCMSmethod j).

Step D:1-(3,4-difluorophenyl)-9-(2-(hydroxynethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecane-2-one

NaOMe (6 mg, 0.116 mmol) was added to a stirred solution of(4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(perfluoroethyl)pyrimidin-2-yl)methylacetate(0.080 g, 0.15 mmol) in MeOH (4 mL). The reaction mixture was allowed tostir at RT for 12 h. Water was added to the reaction mixture and it wasextracted with EtOAc. The extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationby preparative TLC by eluting with EtOAc provided the title compound (19mg, 0.038 mmol) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.40(m, 1H), 7.24 (m, 1H), 7.02 (s, 1H), 6.89-6.92 (m, 1H), 5.02 (t, 1H),4.33 (d, 2H), 3.06 (brs, 2H), 2.41 (t, 2H), 2.10 (d, 2H), 1.97-1.74 (m,4H), 1.4-1.58 (m, 2H); m/z=507.1 [M+H]⁺; t_(R)=1.48 min (LCMS method j).

Example 80:1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 2,4-dichloro-6-(trifluoromethyl)pyrimidine

A mixture of 6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (5.00 g,27.7 mmol), N,N-dimethylaniline (0.260 g, 25.0 mmol) and POCl₃ (15.7 g,103 mmol) in MeCN (25 mL) was heated at 80° C. for 6 h. After cooling toRT, the reaction mixture was concentrated under reduced pressure,diluted with water and extracted with EtOAc twice. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure to provide crude 2,4-dichloro-6-(trifluoromethyl)pyrimidine asbrown oil (6.0 g) which was used for the next step without furtherpurification.

Step B:9-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate A, 1.50 g, 5.35 mmol),2,4-dichloro-6-(trifluoromethyl)pyrimidine (1.16 g, 5.35 mmol) and DIPEA(2.8 mL, 16 mmol) in EtOH (20 mL) was heated at 80° C. for 16 h. Aftercooling to RT, the reaction mixture was diluted with water and extractedtwice with EtOAc. The organic layers were combined, washed with brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by silica gel chromatography (4-12% in MeOH in DCM)provided9-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-oneas an off-white solid (1.37 g). m/z=461.00 [M+H]⁺

Step C:9-(2-((benzyloxy)methyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

To a stirred solution of9-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(0.65 g, 1.4 mmol) in dioxane (4 mL) and water (4 mL) was addedpotassium benzyloxymethyltrifluoroborate (0.97 g, 4.2 mmol) and Cs₂CO₃(1.4 g, 4.2 mmol). The reaction mixture was purged with argon for 5 min.CataCXium-A® (0.10 g, 0.28 mmol) and Pd(OAc)₂ (0.032 g, 0.14 mmol) wasadded and the argon purging continued for 5 min. The reaction mixturewas heated at 120° C. for 18 h. The reaction mixture was cooled to RT,diluted with water and extracted with EtOAc twice. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification by silica gelchromatography (12-65% EtOAc in hexane) provided9-(2-((benzyloxy)methyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(1.36 g). m/z=547.2 [M+H]⁺

Step D:1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of9-(2-((benzyloxy)methyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(1.36 g) and Pd(OH)₂ (2.72 g) in EtOH (40 mL) was placed under atatmosphere of hydrogen (1 atm, balloon) for 18 h. The reaction mixturewas purged with nitrogen, filtered through a celite bed, washed withEtOAc and the clear filtrate was concentrated under reduced pressure.Purification by silica gel chromatography (4-12% MeOH in DCM) provided1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-oneas an off-white solid (0.61 g, 1.1 mmol). m/z=547.1 [M+H]⁺

Step E:4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylicAcid

Jones reagent (1.8 mL) was added to a stirred solution of1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one(0.33 g, 0.72 mmol) in acetone (7 mL). The reaction mixture was stirredat RT for 2 h followed by addition of isopropanol (1.5 mL). The reactionmixture was diluted with water and extracted with EtOAc twice. Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to provide crude4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylicacid (0.230 g, 0.489 mmol) which was used for the next step withoutpurification.

Step F: ethyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylate

A mixture of4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylicacid (0.230 g, 0.489 mmol), Cs₂CO₃ (0.160 g, 0.489 mmol) and ethyliodide (0.060 mL, 0.73 mmol) in DMF (6 mL) was stirred at RT for 16 h.The reaction mixture was diluted with water and extracted with EtOAc.The organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to provide ethyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylateas gummy brown liquid. (0.21 g, 0.42 mmol). m/z=499.1 [M+H]⁺

Step G:1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of ethyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylate(0.21 g, 0.42 mmol) in THF (10 mL) was cooled to 0° C. and treated withMeMgBr (3.0 M in ether, 4 mL, 12 mmol). The reaction temperature wasraised to RT and stirring continued for 18 h. The reaction mixture wasquenched with saturated aqueous NH₄Cl and extracted with EtOAc twice.The combined extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification bypreparative HPLC (LUNA OMEGA, 5.0μ, 21.2×250 mm; water/ACN elution)provided the title compound as an off-white solid (5 mg, 0.010 mmol). ¹HNMR (400 MHz, DMSO-d₆) δ 7.28-7.45 (m, 1H), 7.23-7.27 (m, 1H), 7.03 (s,1H), 6.93 (d, 1H), 3.07 (brs, 2H), 2.43 (t, 2H), 2.14 (brs, 2H),1.84-1.93 (m, 4H), 1.5-1.62 (m, 2H), 1.37 (s, 6H). 2 protons obscured byDMSO peak; m/z=485.2 [M+H]⁺; t_(R)=1.54 min (LCMS method j).

Example 81:1-(4-chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 2-bromo-4-(2,2,2-trifluoroethoxy)pyridine

A solution of NaOtBu (0.529 g, 5.50 mmol) in DMSO (3 mL) was addeddropwise to a solution of 2-bromo-4-fluoropyridine (0.52 mL, 5 mmol) and2,2,2-trifluoroethanol (0.54 mL, 7.5 mmol) in 1 mL of DMSO. The reactionmixture was stirred for 2 h at RT, quenched with ice water, andextracted with DCM. The combined organic extracts were carefullyevaporated (the product is volatile). The crude product was purified bysilica gel chromatography (0-50% EtOAc in cyclohexane) providing2-bromo-4-(2,2,2-trifluoroethoxy)pyridine (1.02 g, 3.78 mmol) as acolorless liquid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.28 (d, 1H), 7.45 (d,1H), 7.19 (dd, 1H), 4.97 (q, 2H) ppm; m/z=256.1 [M+H]⁺; t_(R)=0.96 min(LCMS method a).

Step B:1-(4-chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

1-(4-Chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate A) (119 mg, 0.40 mmol) and NaOtBu (67 mg, 0.70 mmol) werestirred in toluene (3 mL) for 15 min.2-Bromo-4-(2,2,2-trifluoroethoxy)pyridine (138 mg, 0.540 mmol) andbis(tri-tert-butylphosphine)palladium(0) (10 mg, 0.020 mmol) were addedto the white suspension and the mixture was heated for 1 h at 90° C.After cooling to RT the reaction was filtered over celite and thefiltrate concentrated. Purification by SFC (Reprosphere PEI 100 Å, 5 μm,30×250 mm; 6-16% MeOH in CO₂ over 10 min) provided the title compound(97 mg, 0.20 mmol) as a white foam. ¹H NMR (400 MHz, DMSO-d₆) δ=7.91 (d,1H), 7.59 (dd, 1H), 7.24 (dd, 1H), 6.98 (dd, 1H), 6.33 (m, 2H), 4.77 (q,2H), 4.07-4.18 (m, 2H), 2.89 (m, 2H), 2.44 (t, 2H), 2.12 (m, 2H),1.84-1.88 (m, 4H) 1.51-1.59 (m, 2H) ppm; m/z=472.4 [M+H]⁺; t_(R)=0.98min (LCMS method a).

Example 82:1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidine

NaH (60% in mineral oil, 831 mg, 20.8 mmol) was added in portions to astirred solution of 4,6-dichloropyrimidine (1.769 g, 11.88 mmol) and2,2,2-trifluoroethanol (1.0 g, 9.9 mmol) in THF (100 mL) at 0° C. Thereaction mixture was allowed to warm to RT and stir overnight. Thereaction mixture was quenched with saturated NH₄Cl solution, dilutedwith EtOAc and extracted twice with EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated. Purification bysilica gel chromatography (0-7% EtOAc in cyclohexane) provided4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidine (1.51 g, 6.75 mmol). ¹H NMR(400 MHz, DMSO-d₆) δ=8.77 (s, 1H), 7.44 (s, 1H), 5.12 (q, 2H) ppm;m/z=213.0 [M+H]⁺; t_(R)=0.96 min (LCMS method a).

Step B:1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (Intermediate A,750 mg, 2.68 mmol), 4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidine (1.137g, 3.75 mmol) and triethylamine (1.12 mL, 8.03 mmol) were dissolved EtOH(10 mL) and heated under microwave irradiation for 30 min at 160° C.After cooling to RT, the reaction mixture was concentrated. Purificationby silica gel chromatography (0-10% MeOH in DCM) provided the titlecompound (667 mg, 2.26 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ=8.20 (s, 1H),7.41 (m, 1H), 7.23 (m, 1H), 6.87-6.94 (m, 1H), 6.18 (s, 1H), 4.93 (q,2H), 4.11-4.34 (m, 2H), 2.99 (br t, 2H), 2.42 (t, 2H), 2.12 (m, 2H),1.80-1.90 (m, 4H) 1.42-1.56 (m, 2H) ppm; m/z=457.2 [M+H]⁺; t_(R)=1.07min (LCMS method a).

By employing similar methods as described for the preparation of Example82, using appropriate starting materials, the following compounds wereprepared:

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 83

473.3; 1.14 min, LCMS method a ¹H NMR (400 MHz, DMSO-d₆) δ = 8.21 (s,1H), 7.59 (dd, 1H), 7.24 (dd, 1H), 6.95 (d, 1H), 6.19 (s, 1H), 4.94 (q,2H), 4.14-4.32 (m, 2H), 2.99 (br t, 2H), 2.43 (t, 2H), 2.14 (m, 2H),1.86 (m, 4H) 1.50 (m, 2H). ppm. 84

455.2; 1.05 min, LCMS method a ¹H NMR (400 MHz, DMSO-d₆) δ = 8.19 (s,1H), 7.58 (t, 1H), 7.23 (dd, 1H), 6.95 (d, 1H), 6.31 (m, 1H), 6.12 (s,1H), 4.51 (dt, 2H), 4.48 (m, 2H), 2.98 (br t, 2H), 2.43 (t, 2H), 2.13(m, 2H), 1.86 (m, 4H) 1.53-1.50 (m, 2H). ppm. 85

417.3; 0.68 min, LCMS method i ¹H NMR (400 MHz, DMSO- d6) δ 8.00 (d, J =5.8 Hz, 1H), 7.42 (dt, J = 10.8, 9.0 Hz, 1H), 7.23 (ddd, J = 11.4, 7.5,2.5 Hz, 1H), 6.92 (ddd, J = 8.3, 4.2, 2.1 Hz, 1H), 5.98 (d, J = 5.8 Hz,1H), 4.58-4.41 (m, 2H), 4.15 (t, J = 6.6 Hz, 2H), 2.97 (td, J = 13.3,2.5 Hz, 2H), 2.43 (t, J = 6.8 Hz, 2H), 2.14 (s, 2H), 1.95-1.77 (m, 4H),1.66 (h, J = 7.1 Hz, 2H), 1.49 (td, J = 13.5, 4.9 Hz, 2H), 0.91 (t, J =7.4 Hz, 3H). 86

471.2; 0.68 min, LCMS method i ¹H NMR (400 MHz, chloroform-d) δ 8.22 (s,1H), 7.17 (m, 1H), 6.89 (m, 1H), 6.76-6.78 (m, 1H), 5.81 (s, 1H), 5.73(m, 1H), 4.22 (t, 2H), 3.05-2.89 (m, 2H), 2.61 (t, 2H), 2.13-2.15 (m,2H), 1.93-1.98 (m, 2H), 1.85- 1.71 (m, 4H), 1.44 (d, 3H). 87

459.4; 1.94 min, LCMS method k ¹H NMR (400 MHz, methanol- d₄) δ 8.11 (s,1H), 7.44-7.36 (m, 1H), 7.28-7.2 (m, 1H), 6.92 (m, 1H), 5.98 (s, 1H),5.28-5.15 (m, 1H), 4.24- 4.1 (m, 2H), 3.83-3.79 (m, 2H), 3.43 (t, 2H),2.93 (t, 2H), 2.41 (t, 2H), 2.12 (br, 2H), 1.98-1.8 (m, 6H), 1.6-1.41(m, 4H). 88

491.08; 0.71 min, LCMS method i 1H NMR (DMSO-d₆, 300 MHz) δ 7.46-7.40(m, 1H), 7.28-7.2 (m, 1H), 6.93- 6.91 (m, 1H), 6.29 (s, 1H), 4.98 (q,2H), 4.4 (br, 2H), 3.04 (t, 2H), 2.43 (t, 2H), 2.13 (br, 2H), 1.9-1.83(m, 4H), 1.48 (br, 2H).

Example 89a:(S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-oneor(R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

and

Example 89b:(R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-oneor(S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 2,2,2-trifluoro-1-(oxetan-3-yl)ethan-1-ol

A solution of oxetane-3-carbaldehyde (1.80 g, 20.9 mmol) in THF (8 mL)was cooled to −70° C. and treated with trimethyl(trifluoromethyl)silane(5.94 g, 41.8 mmol) followed by tetrabutylammonium fluoride (5.46 g,20.9 mmol). The reaction was warmed to RT, and stirred for 3 h. Thereaction mixture was diluted with water, and extracted twice with EtOAc.The combined organic layers were washed with brine solution, dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure toafford 2,2,2-trifluoro-1-(oxetan-3-yl)ethan-1-ol (2.8 g, crude).

Step B:4-chloro-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-2-amine

A stirred solution of 4,6-dichloropyrimidin-2-amine (2.20 g, 13.4 mmol)and 2,2,2-trifluoro-1-(oxetan-3-yl)ethan-1-ol (2.72 g, 17.4 mmol) in1,4-dioxane (10 mL) was treated with Cs₂CO₃ (13.11 g, 40.24 mmol). Thereaction mixture was heated to 80° C. for 12 h. The reaction mixture wascooled to RT, diluted with water, and extracted twice with EtOAc. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationby silica gel chromatography (1% MeOH in DCM) provided4-chloro-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-2-amine(2.10 g, 55.2%). m/z=284.0, [M−H]⁺; t_(R)=1.45 min (LCMS method l)

Step C:9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of4-chloro-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-2-amine(0.303 g, 1.07 mmol) and1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (Intermediate A,0.300 g, 1.07 mmol) was treated with Cs₂CO₃ (1.04 g, 3.21 mmol). Thereaction mixture was heated to 80° C. for 15 h. The mixture was cooledto RT, diluted with water, and extracted twice with EtOAc. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. Purification bypreparative HPLC (GEMINI, 5 μm, 21.2×150 mm; water/ACN elution) providedpure racemic material. ¹H NMR (300 MHz, DMSO-d₆) δ 7.40 (m, 1H), 7.21(m, 1H), 6.94-6.82 (m, 1H), 6.22 (s, 2H), 6.12 (m, 1H), 5.44 (s, 1H),4.69-4.47 (m, 3H), 4.35 (t, 1H), 4.13 (brs, 2H), 3.57 (m, 1H), 2.87 (t,2H), 2.39 (t, 2H), 2.08 (s, 2H), 1.72-1.82 (m, 4H), 1.55-1.34 (m, 2H).m/z=528.1, [M+H]⁺, t_(R)=1.53 min (LCMS method l). Chiral SFC (CHIRALPAK IA, 10 μm, 10×250 mm; mobile phase A: CO₂, mobile phase B: IPA; flowrate 15 mL/min; isocratic elution A:B 77:23) provided Example 89a (peak1, 27 mg; SFC t_(R)=10.23 min) and Example 89b (peak 2, 28 mg; SFCt_(R)=10.94 min).

By employing similar methods as described for the preparation ofExamples 89a and 89b, using appropriate starting materials, thefollowing compounds were prepared:

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 90

480.3; 0.55 min, LCMS method i ¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (m, 1H),7.23 (m, 1H), 6.91 (m, 1H), 6.03 (s, 2H), 5.28 (s, 1H), 5.03-4.88 (m,1H), 4.11 (brs, 2H), 2.97- 3.06 (m, 2H), 2.84 (t, 2H), 2.55-2.63 (m,2H), 2.41 (t, 2H), 2.08 (d, 2H), 1.78-1.85 (m, 4H), 1.43 (t, 2H). 91

472.2; 0.61 min, LCMS method i ¹H NMR (400 MHz, chloroform-d) δ 7.21(dtd, J = 10.0, 8.6, 3.4 Hz, 1H), 6.90 (ddd, J = 10.6, 7.1, 2.5 Hz, 1H),6.80 (dddd, J = 8.4, 4.0, 2.5, 1.7 Hz, 1H), 5.37 (s, 1H), 4.68 (dq, J =12.9, 8.5 Hz, 2H), 4.16 (dd, J = 28.3, 13.7 Hz, 2H), 3.01 (d, J = 14.5Hz, 2H), 2.62 (td, J = 6.8, 3.6 Hz, 2H), 2.19-2.10 (m, 2H), 2.01- 1.86(m, 3H), 1.83 (s, 3H). 92

474.2; 0.59 min, LCMS method i ¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (m, 1H),7.23 (m, 1H), 6.91 (m, 1H), 6.18 (s, 2H), 5.40 (s, 1H), 4.1-4.18 (m,2H), 2.87 (t, 2H), 2.41 (t, 2H), 2.08-2.12 (m, 2H), 1.82 (m, 4H),1.38-1.5 (m, 2H). 93

432.3; 0.49 min, LCMS method i ¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (m, 1H),7.23 (m, 1H), 6.91 (m, 1H), 5.92 (s, 2H), 5.18 (s, 1H), 5.12 (h, 1H),4.18-3.97 (m, 2H), 2.82 (t, 2H), 2.41 (t, 2H), 2.15-2.02 (m, 2H),1.91-1.75 (m, 4H), 1.4-1.45 (m, 2H), 1.16 (d, 6H). 94

434.1; 0.42 min, LCMS method i ¹H NMR (DMSO-d₆, 300 MHz) δ 7.42-7.36 (m,1H), 7.24- 7.18 (m, 1H), 6.91-6.88 (m, 1H), 6.17 (br, 2H), 5.3 (s, 1H),4.7 (br, 1H), 4.18-4.08 (m, 4H), 3.57 (t, 2H), 2.86 (t, 2H), 2.41-2.37(m, 2H), 2.07 (br, 2H), 1.81-1.77 (m, 4H), 1.46- 1.38 (m, 2H). 95

486.2; 0.68 min, LCMS method i ¹H NMR (600 MHz, chloroform-d) δ 7.16 (m,1H), 6.87 (m, 1H), 6.76 (d, 1H), 4.80 (s, 2H), 4.69-4.56 (m, 4H), 3.06(t, 2H), 2.86 (t, 2H), 2.60 (t, 2H), 2.13 (brs, 2H), 1.88-1.98 (m, 4H),1.80- 1.72 (m, 6H). 96

542.3; 2.05 min, LCMS method k ¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (m, 1H),7.23 (m, 1H), 6.91 (m, 1H), 6.25 (s, 2H), 6.14 (m, 1H), 5.44 (s, 1H),4.61 (d, 1H), 4.47 (d, 1H), 4.21 (d, 2H), 4.13 (d, 2H), 2.88 (t, 2H),2.41 (t, 2H), 2.15- 2.04 (m, 2H), 1.89-1.76 (m, 3H), 1.46 (s, 4H). 97

522.2; 0.64 min. LCMS method i ¹H NMR (300 MHz, DMSO-d₆) δ□7.41 (m, 1H),7.22 (m, 1H), 6.91 (m, 1H), 6.20 (s, 2H), 5.38 (s, 1H), 4.92 (t, 2H),4.25- 4.00 (m, 2H), 2.88 (t, 2H), 2.41 (t, 2H), 2.18-2.04 (brs, 2H),1.72-1.9 (m, 4H), 1.36- 1.5 (m, 2H). 98

496.3; 1.16 min, LCMS method k ¹H NMR (300 MHz, DMSO-d₆) δ 7.45 (m, 1H),7.23 (m, 1H), 6.91 (m, 1H), 6.11 (s, 2H), 5.49 (dt, 1H), 5.36 (s, 1H),4.29 (m, 1H), 4.22-3.69 (m, 4H), 2.87 (t, 2H), 2.47-2.33 (m, 2H), 2.09(d, 2H), 1.72- 1.88 (m, 4H), 1.38-1.5 (m, 2H). 99

492.3; 0.51 min, LCMS method i ¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (m, 1H),7.23 (m, 1H), 6.91 (d, 1H), 6.05 (s, 2H), 5.29 (s, 1H), 5.19-5.22 (m,1H), 4.58 (d, 1H), 4.11 (brs, 2H), 3.82-3.94 (m, 2H), 3.77- 3.64 (m,1H), 3.55-3.42 (m, 2H), 2.85 (t, 2H), 2.41 (t, 2H), 2.15-2.01 (m, 3H),1.77- 1.88 (m, 3H) 100

474.3; 0.79 min, LCMS method k ¹H NMR (300 MHz, DMSO-d₆) δ 7.39 (m, 1H),7.20 (m, 1H), 6.94-6.81 (m, 1H), 5.96 (s, 2H), 5.21 (s, 1H), 4.8-4.9 (m,1H), 3.74 (dd, 2H), 3.51- 3.62 (m, 1H), 3.35-3.46 (m, 1H), 3.26-3.32 (m,1H), 2.81 (t, 2H), 2.39 (t, 3H), 1.67- 1.88 (m, 8H), 1.32-1.5 (m, 4H).101

474.4; 0.17 min, LCMS method l ¹H NMR (400 MHz, DMSO-d₆) δ 7.37 (m, 1H),7.21 (m, 1H), 6.90 (m, 1H), 5.22 (s, 1H), 4.98-5.03 (m, 1H), 4.09 (d,2H), 3.75-3.82 (m, 2H), 3.42- 3.34 (m, 4H), 2.82 (t, 2H), 2.40 (t, 2H),2.15-1.99 (m, 2H), 1.93-1.71 (m, 5H), 1.41- 1.52 (m, 3H). 102

478.3; 0.52 min, LCMS method i ¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (m, 1H),7.23 (m, 1H), 6.91 (m, 1H), 6.11 (s, 2H), 5.41 (dd, 2H), 5.28 (m, 1H),5.14 (d, 1H), 4.02-4.14 (m, 2H), 3.86-3.94 (m, 2H), 3.68- 3.72 (m, 1H),3.62-3.68 (m, 1H), 2.85 (t, 2H), 2.41 (t, 2H), 2.09 (s, 2H), 1.77-1.81(m, 4H), 1.48-1.52 (d, 2H).

Example 103:9-(2-amino-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: tert-butyl(tert-butoxycarbonyl)(4,6-dichloropyrimidin-2-yl)carbamate

A stirred solution of 4,6-dichloropyrimidin-2-amine (10.00 g, 60.97mmol) in THF (100 mL), was treated with DMAP (0.744 g, 6.10 mmol) anddi-tertbutyl dicarbonate (29.27 g, 134.1 mmol) and stirred at RT for 12h. The reaction was quenched by addition of ice and it was thenextracted with EtOAc. The combined extracts were washed with aqueousNaHCO₃, dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. Purification by silica gel chromatography (10% EtOAcin hexane) provided tert-butyl(tert-butoxycarbonyl)(4,6-dichloropyrimidin-2-yl)carbamate (16.23 g) aslight brown liquid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (s, 1H), 1.4 (s,18H).

Step B: tert-butyl(tert-butoxycarbonyl)(4-chloro-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-2-yl)carbamate

A stirred solution of tert-butyl(tert-butoxycarbonyl)(4,6-dichloropyrimidin-2-yl)carbamate (0.500 g,1.37 mmol) in dioxane (7 mL) was treated withtetrahydro-2H-pyran-4-d-4-ol (0.170 g, 1.65 mmol) and Cs₂CO₃ (1.342 g,4.118 mmol). The reaction mixture was stirred at 80° C. for 12 h. Thereaction mixture was cooled to RT, diluted with water, and extractedtwice with EtOAc. The combined organic extracts were washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The crude material (0.56 g) was used as such for the next stepwithout any purification. m/z=431.1, [M+H]⁺; t_(R)=1.68 min (LCMS methodj).

Step C: tert-butyl(tert-butoxycarbonyl)(4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-2-yl)carbamate

1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (Intermediate A,0.300 g, 1.07 mmol) and DIPEA (0.56 mL, 3.2 mmol) were added to astirred solution of tert-butyl(tert-butoxycarbonyl)(4-chloro-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-2-yl)carbamate(0.553 g, 1.28 mmol) in EtOH (7 mL). The reaction mixture was heated to80° C. for 12 h. The reaction mixture was cooled to RT, diluted withwater and extracted twice with EtOAc. The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The crude material (0.788 g) was used as such for thenext step without purification. m/z=675.2, [M+H]⁺; t_(R)=1.60 min (LCMSmethod j).

Step-D:9-(2-amino-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of hydrochloric acid (4.0 M in dioxane, 15 mL) was added to astirred solution of tert-butyl(tert-butoxycarbonyl)(4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-2-yl)carbamate(0.780 g, 1.16 mmol) in dioxane (5 mL). The reaction mixture was stirredat RT for 12 h. The reaction mixture was concentrated under reducedpressure and the residue slurried with saturated aqueous NaHCO₃. Themixture was extracted with EtOAc. The combined extracts were washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. Purification by preparative HPLC (LUNA Phenomenex, 5.0μm, 21.2×250 mm; 0.01% HCOOH in water:ACN elution) provided the titlecompound as an off-white solid (78 mg). ¹H NMR (300 MHz, DMSO-d₆) δ 8.26(brs, 2H), 7.42 (m, 1H), 7.23 (m, 1H), 6.91 (m, 1H), 5.23 (s, 1H), 4.11(d, 2H), 3.80 (dt, 2H), 3.40 (t, 2H), 2.83 (t, 2H), 2.41 (t, 2H),2.02-2.12 (m, 2H), 1.71-1.9 (m, 6H), 1.35-1.52 (m, 4H); m/z=475.2[M+H]⁺; t_(R)=1.31 min (LCMS method j).

Example 104:rac-9-(2-amino-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step-A: 4-fluoro-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-2-amine

Sodium hydride (0.183 g, 7.63 mmol) was added portion-wise to a stirredsolution of 3-methyltetrahydrofuran-3-ol (0.311 g, 3.05 mmol) in THF (5mL) at 0° C., and stirred at the same temperature for 30 minutes. Asolution of 4,6-difluoropyrimidine-2-amine (0.200 g, 1.52 mmol) in THF(5 mL) was added and the mixture was stirred at RT for 16 h. Saturatedaqueous NH₄Cl was added and the mixture was extracted twice with EtOAc.The combined organic extracts were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by preparative TLC (30% EtOAc in hexane) provided4-fluoro-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (0.163g) as an off-white solid. m/z=214.2 [M+H]⁺; t_(R)=0.41 min (LCMS methodl).

Step-B:9-(2-amino-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (Intermediate A,0.214 mg, 0.764 mmol) and DIPEA (0.40 mL, 2.3 mmol) were added to astirred solution of4-fluoro-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (0.163mg, 0.764 mmol) in EtOH (1 mL) at RT. The reaction mixture was heated at80° C. for 48 h. The mixture was cooled to RT, diluted with water andextracted twice with EtOAc. The combined organic extracts were washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude product was purified by preparativeTLC (10% MeOH in DCM) to provide the title compound (0.125 mg) as anoff-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.42 (m, 1H), 7.23 (m, 1H),6.91 (ddd, 1H), 5.93 (s, 2H), 5.19 (s, 1H), 4.09 (d, 2H), 3.92 (d, 1H),3.70-3.78 (m, 3H), 2.82 (t, 2H), 2.48-2.27 (m, 4H), 2.05-2.15 (m, 2H),1.72-1.9 (m, 4H), 1.59 (s, 3H), 1.32-1.5 (m, 2H); m/z=474.3 [M+H]⁺;t_(R)=0.50 min (LCMS method i).

Example 105:rac-9-(2-amino-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 6-chloro-2-(methylthio)pyrimidin-4-ol

A stirred solution of 4,6-dichloro-2 (methylthio)pyrimidine (5.0 g, 25.6mmol) in 2 M NaOH (125 mL) was heated at 120° C. for 5 h. The reactionmixture was cooled to RT and acidified to pH 6 by slow addition of AcOH.The white solid obtained was isolated by filtration and dried undervacuum to provide 6-chloro-2-(methylthio)pyrimidin-4-ol as an off-whitesolid (4.07 g, crude). ¹H NMR (300 MHz, DMSO-d₆) δ 13.1 (brs, 1H), 6.22(s, 1H), 2.5 (s, 3H).

Step B:4-chloro-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylthio)pyrimidine

A stirred solution of 6-chloro-2-(methylthio)pyrimidin-4-ol (3.40 g,32.0 mmol) and triphenyl phosphine (11.6 g, 44.2 mmol) in THF (100 mL)was treated with (3R,4R)-4-fluorotetrahydrofuran-3-ol (2.00 g, 11.3mmol) and DIAD (7.67 g, 37.9 mmol). The reaction mixture was heated to80° C. for 12 h. After cooling to RT, the mixture was diluted withpentane and the solvent was decanted. The decanted solvent wasconcentrated under reduced pressure. Purification by silica gelchromatography (10% EtOAc in hexane) provided4-chloro-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylthio)pyrimidineas an off-white solid (1.82 g). ¹H NMR (300 MHz, DMSO-d₆) δ 6.96 (s,1H), 5.59-5.32 (m, 2H), 4.11-4.01 (m, 2H), 3.97-3.78 (m, 2H), 2.53 (s,3H).

Step C:4-chloro-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylsulfonyl)pyrimidine

A stirred solution of4-chloro-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylthio)pyrimidine(1.80 g, 6.80 mmol) in THF (30 mL) and water (7 mL) was treated withOxone® (6.20 g, 20.4 mmol). The reaction mixture was stirred at RT for 3h, after which time it was diluted with water and extracted twice withEtOAc. The organic extracts were washed with NaHCO₃ solution, brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The crude material (1.86 g) was used as such for the next stepwithout any purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.68 (s, 1H),5.65-5.41 (m, 2H), 4.14-3.87 (m, 4H), 3.45 (s, 3H).

Step D:1-(3,4-difluorophenyl)-9-(6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of4-chloro-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylsulfonyl)pyrimidine(1.00 g, 3.57 mmol),1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (Intermediate A,1.06 g, 3.57 mmol) and DIPEA (1.38 g, 10.7 mmol) in EtOH (8 mL) washeated at 80° C. for 1 h. The reaction mixture was cooled to RT, dilutedwith water, and extracted twice with EtOAc. The combined extracts werewashed with NaHCO₃ solution, brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to provide1-(3,4-difluorophenyl)-9-(6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one(0.643 g). m/z=541.1 [M+H]⁺; t_(R)=0.93 min (LCMS method l).

Step E:9-(2-azido-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of1-(3,4-difluorophenyl)-9-(6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one(0.640 g, 1.18 mmol) and sodium azide (0.900 g, 13.8 mmol) in DMF (15mL) was heated at 50° C. for 24 h. The reaction mixture was cooled toRT, diluted with water, and extracted twice with EtOAc. The extractswere washed with aqueous NaHCO₃, brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The crude material(0.651 g) was used as such for the next step without furtherpurification. m/z=504.4 [M+H]⁺; t_(R)=2.18 min (LCMS method l).

Step F:9-(2-amino-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of9-(2-azido-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(0.651 g, 1.29 mmol) in THF (6 mL) was cooled to −78° C. Trimethylphosphine (0.108 g, 1.42 mmol) was added and the temperature wasgradually raised to RT. The mixture was stirred at RT for 12 h, thenheated at 50° C. for 24 h. The reaction mixture was cooled to RT,diluted with water, and extracted twice with EtOAc. The extracts werewashed with NaHCO₃ solution, brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. Purification bypreparative HPLC (Acquity XSelect, 5.0 μm, 21.2×250 mm; mobile phase0.02% NH₄OH in water:ACN) provided the title compound (0.356 g) as anoff-white solid. ¹H NMR (300 MHz, chloroform-d) δ 7.17 (m, 1H), 6.88 (m,1H), 6.77 (m, 1H), 5.34 (m, 2H), 5.17 (m, 1H), 4.56 (s, 2H), 4.22-4.07(m, 3H), 4.06-3.94 (m, 1H), 3.87-3.76 (m, 2H), 2.8-2.95 (m, 2H), 2.60(t, 2H), 2.18-2.05 (m, 2H), 1.88-1.95 (m, 2H), 1.7-1.78 (m, 4H);m/z=478.2 [M+H]⁺, t_(R)=0.50 min (LCMS method i).

Example 106:1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: methyl4-chloro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate

A mixture of methyl 4,6-dichloropyrimidine-2-carboxylate (300 mg, 1.45mmol), tetrahydro-2H-pyran-4-ol (148 mg, 1.45 mmol) and Cs₂CO₃ (944 mg,2.90 mmol) in dioxane (5 mL) was heated to 80° C. for 2 h. The reactionmixture was cooled to RT, diluted with water and extracted twice withEtOAc. The combined organic extracts were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure toprovide methyl4-chloro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate (130mg) which was used without purification.

Step B: methyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate

A mixture of methyl4-chloro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate (130mg, 0.476 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate A, 133 mg, 0.476 mmol) and DIPEA (0.18 mL, 1.4 mmol) inEtOH was heated at 80° C. for 2 h. The reaction mixture was cooled toRT, diluted with water and extracted twice with EtOAc. The combinedorganic extracts were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to provide methyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate(120 mg, crude). m/z=517.2 [M+H]⁺; t_(R)=1.31 min (LCMS method k).

Step-C:1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of methyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate(120 mg, 0.232 mmol) in MeOH (5 mL) was treated with sodium borohydride(35 mg, 0.93 mmol) at 0° C. The mixture was stirred at RT for 2 h. Themixture was diluted with water and extracted twice with EtOAc. Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationby preparative HPLC (LUNA C18, 5 μm, 21.2×250 mm; 0.1% HCOOH:MeCNelution) provided the title compound (5 mg). ¹H NMR (400 MHz, DMSO-d₆) δ7.42 (m, 1H), 7.24 (m, 1H), 6.90-6.92 (m, 1H), 5.84 (s, 1H), 5.11-5.2(m, 1H), 4.70 (t, 1H), 4.23 (d, 3H), 3.78-3.83 (m, 2H), 3.45 (t, 2H),2.92 (t, 2H), 2.42 (t, 2H), 2.11 (brs, 2H), 1.83-1.92 (m, 5H), 1.57-1.57(m, 4H); m/z=489.3 [M+H]⁺; t_(R)=1.1 min (LCMS method k).

By employing similar methods as described for the preparation of Example106, using appropriate starting materials, the following compounds wereprepared:

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 107

507.3; 0.57 min, LCMS method i ¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (m, 1H),7.25 (m, 1H), 6.92 (d, 1H), 5.92 (s, 1H), 5.25-5.32 (m, 1H), 4.82 (d,1H), 4.74 (t, 1H), 4.24 (d, 3H), 3.84-3.98 (m, 2H), 3.46- 3.65 (m, 2H),2.94 (t, 2H), 2.42 (t, 2H), 2.11 (brs, 2H), 1.83-1.91 (m, 4H), 1.41-1.52 (m, 2H). 108

493.2; 0.58 min, LCMS method i ¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (m, 1H),7.24 (m, 1H), 6.92 (d, 1H), 5.92 (s, 1H), 5.52 (d, 1H), 5.25 (d, 1H),4.78 (t, 1H), 4.26 (d, 2H), 4.13 (dd, 1H), 4.02-3.78 (m, 2H), 3.68 (d,1H), 2.94 (t, 2H), 2.42 (t, 2H), 2.12 (brs, 2H), 1.80-1.88 (m, 3H), 1.46(t, 2H). 109

475.2; 0.55 min, LCMS method i ¹H NMR (300 MHz, methanol- d₄) δ 7.27 (m,1H), 7.05 (m, 1H), 6.95 (m, 1H), 5.78 (s, 1H), 5.52 (m, 1H), 4.38 (s,2H), 4.3 (m, 2H), 3.82-3.95 (m, 4H), 3.02 (t, 2H), 2.56 (t, 2H),2.18-2.25 (m, 3H), 1.88- 2.01 (m, 5H), 1.7 (brs, 2H).

Example 110a:(S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-oneor(R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

and

Example 110b:(R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-oneor(S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Racemic1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-oneor(R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-onewas synthesized in a manner similar to that employed for Example 106using rac-1,1,1-trifluoropropan-2-ol. ¹H NMR (400 MHz, DMSO-d₆) δ 7.42(m, 1H), 7.24 (m, 1H), 6.98-6.84 (m, 1H), 6.00 (s, 1H), 5.94 (m, 1H),4.84 (t, 1H), 4.26 (d, 3H), 2.96 (t, 2H), 2.42 (t, 2H), 2.18-2.04 (m,2H), 1.91-1.78 (m, 4H), 1.47 (t, 2H), 1.37 (d, 3H); m/z=501.1 [M+H]⁺;t_(R)=1.63 (LCMS method l). The racemic product was purified by chiralHPLC (Phenomenex Lux Cellulose, 4 μm, 21.2×250 mm; mobile phase A:hexane, mobile phase B: EtOH; isocratic elution 70(A):30(B); flow rate15 mL/min) to provide Example 110b (peak 1; chiral HPLC t_(R)=3.57 min),and Example 110a (peak 2; chiral HPLC t_(R)=3.94 min).

Example 111: rac ethyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(((3S,4S)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate

Step A: rac-(3R,4R)-4-fluorotetrahydrofuran-3-ol

Triethylaminetrihydrofluoride (60 mL) was added to3,6-dioxabicyclo[3.1.0]hexane (10.00 g, 116.1 mmol) at RT. The mixturewas then heated at 120° C. for 12 h. The reaction was quenched by icecold water and extracted with EtOAc. The extracts were washed withbrine, and dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purification by silica gel chromatography (100% EtOAc)provided rac-(3R,4R)-4-fluorotetrahydrofuran-3-ol (8.0 g) as a brownliquid. ¹H NMR (300 MHz, DMSO-d₆) δ 5.42 (d, 1H), 5.21-5.25 (m, 1H),3.77-3.9 (m, 2H), 3.53-3.56 (m, 1H), 3.34 (br s, 1H).

Step B: rac-methyl4-chloro-6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate

A mixture of methyl 4,6-dichloropyrimidine-2-carboxylate (0.150 g, 0.724mmol), rac-(3R,4R)-4-fluorotetrahydrofuran-3-ol (0.076 g, 0.72 mmol) andCs₂CO₃ (0.472 g, 1.45 mmol) in dioxane (5 mL) was stirred at RT for 3 h.The reaction was diluted with water and extracted with EtOAc. Theextracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide rac-methyl4-chloro-6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate(0.160 g) as yellow gummy solid which as taken on without furtherpurification. m/z=277.1 [M+H]⁺; t_(R)=0.47 min (LCMS method l).

Step C: rac-ethyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(((3S,4S)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one(Intermediate A, 0.045 g, 0.16 mmol), rac-methyl4-chloro-6-(((3R,4R)-4-fluorotrtrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate(0.060 g, 0.22 mmol) and DIPEA (110 μL, 0.65 mmol) in EtOH (2 mL) washeated at 80° C. for 2 hours. The mixture was cooled to RT, diluted withwater and extracted with EtOAc. The extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by preparative HPLC (LUNA Phenomenex, 5 μm, 21.2×250 mm;0.1% HCOOH in H₂O:ACN elution) provided the title compound (3 mg) as anoff-white solid. ¹H NMR (400 MHz, methanol-d₄) δ 7.24 (m, 1H), 7.09 (m,1H), 6.91 (m, 1H), 6.07 (s, 1H), 5.54-5.58 (m, 1H), 5.2 (d, 1H),4.22-4.34 (m, 4H), 4.17-4.22 (m, 1H), 4.03 (s, 1H), 3.92-3.94 (m, 1H),3.8 (d, 1H), 3.07 (t, 2H), 2.57 (t, 2H), 2.18-2.3 (m, 2H), 1.91-2.01 (m,4H), 1.7 (brs, 2H), 1.29 (m, 3H); m/z=535.3 [M+H]⁺; t_(R)=2.13 min (LCMSmethod l).

Example 112:(R)-9-(2-amino-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: (R)-6-chloro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine

A mixture of 4,6-dichloropyrimidin-2-amine (0.300 g, 1.83 mmol),(R)-tetrahydrofuran-3-amine (0.120 g, 1.37 mmol) and DIPEA (0.96 mL, 5.5mmol) in EtOH (5 mL) was heated at 80° C. for 12 h. The reaction mixturewas cooled to RT, diluted with water and extracted twice with EtOAc. Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was triturated with pentane to afford(R)-6-chloro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (0.25 g,64%) as an off-white solid. m/z=215.0 [M+H]⁺; t_(R)=0.64 min (LCMSmethod l).

Step B: (R)-6-fluoro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine

A mixture of(R)-6-chloro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (0.100 g,0.465 mmol) and CsF (0.283 g, 1.86 mmol) in DMSO (5 mL) was heated at150° C. for 24 h. The reaction mixture was cooled to RT, diluted withwater and extracted twice with EtOAc. The combined organic extracts werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. Washing of the crude product withpentane to provided(R)-6-fluoro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (0.15 g,crude). m/z=199.2 [M+H]⁺; t_(R)=0.43 min (LCMS method k).

Step C:(R)-9-(2-amino-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of(R)-6-fluoro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (0.100 g,0.502 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate A, 0.106 g, 0.376 mmol) and DIPEA (0.26 mL, 1.5 mmol) inEtOH (3 mL) was heated to 80° C. for 72 h. The reaction mixture wascooled to RT, diluted with water and extracted twice with EtOAc. Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationby preparative HPLC (Waters XSelect, 5 μm, 21.2×250 mm; mobile phase0.02% NH₄OH in H₂O:ACN) provided the title compound as an off-whitesolid (20 mg). ¹H NMR (300 MHz, DMSO-d₆) δ 7.43 (m, 1H), 7.24 (m, 1H),6.92 (s, 1H), 6.34 (d, 1H), 5.46 (s, 2H), 4.94 (s, 1H), 4.26 (s, 1H),4.01 (d, 1H), 3.6-3.82 (m, 2H), 2.87-2.56 (m, 3H), 2.32-2.54 (m, 2H),2.16-1.92 (m, 3H), 1.6-1.76 (m, 4H), 1.44 (s, 3H), 1.32-1.5 (m, 2H);m/z=459.2 [M+H]⁺; t_(R)=1.30 min (LCMS method j).

Example 113a:(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one,or(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one

and

Example 113b:(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one,or(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one

Step A:rac-4-chloro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-2-amine

To a solution of 4,6-dichloropyrimidin-2-amine (5.00 g, 30.5 mmol) in1,4-dioxane (125 mL) was added 1,1,1-trifluoropropan-2-ol (5.20 g, 45.7mmol) and Cs₂CO₃ (29.80 g, 91.46 mmol). The mixture was stirred at 80°C. for 16 h. The reaction mixture was cooled to RT, diluted with water,and extracted with EtOAc. The combined organic extracts were washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducepressure to provide4-chloro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-2-amine (7.40 g)as a yellow solid. m/z=242.1 [M+H]⁺; t_(R)=0.76 min (LCMS method l).

Step B:rac-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecane-2-one

To a suspension ofrac-4-chloro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-2-amine (7.40g, 29.4 mmol) in EtOH (200 mL) was added1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecane-2-one(Intermediate E, 9.40 g, 29.4 mmol). DIEA (26.60 g, 205.7 mmol) wasadded dropwised at 25° C. The mixture was stirred at 80° C. for 24 h.After cooling to RT, the reaction mixture was concentrated under reducedpressure. Purification by silica gel chromatography (100% EtOAc)provided racemic9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one(4.4 g) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.49-7.29 (m,2H), 7.00-7.03 (m, 1H), 6.17 (s, 2H), 5.65-5.78 (m, 1H), 5.37 (s, 1H),4.35 (t, 2H), 4.15 (brs, 2H), 2.83 (t, 2H), 2.30 (t, 2H), 1.84 (d, 2H),1.47-1.35 (m, 2H), 1.32 (d, 3H); m/z=488.2 [M+H]⁺; t_(R)=0.64 min (LCMSmethod i). Chiral SFC (Waters UPCC; Chiralpak IG-3, 3 μm, 4.6×250 mm,35° C.; mobile phase A: CO₂, mobile phase B: 0.1% DEA in MeOH, isocraticelution: 40% B for 7 min; flow rate 2.5 mL/min; UV detection, 210 nm)provided Example 113a (peak 1, 0.974 g; SFC t_(R)=4.41 min), and Example113b (peak 2, 1.20 g; SFC t_(R)=5.10 min).

The synthesis of Example 114 was accomplished by employing similarmethods as described for the preparation of Examples 65 and 66 usingIntermediate E. The synthesis of Example 115 was accomplished byemploying similar methods as described for the preparation of Example64, using Intermediate E.

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 114

525.2; 0.64 min, LCMS method i ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H),8.30 (s, 1H), 7.51-7.32 (m, 2H), 7.03- 7.07 (m, 1H), 6.98 (s, 1H), 4.98(brs, 1H), 4.49-4.24 (m, 5H), 3.08 (t, 2H), 2.38 (t, 3H), 1.98 (d, 2H),1.42-1.6 (m, 2H). 115

510.2; 0.65 min, LCMS method i ¹H NMR (300 MHz, chloroform-d) δ 8.72 (s,1H), 7.84 (s, 1H), 7.13-7.22 (m, 1H), 6.86-7.01 (m, 2H), 6.52 (s, 1H),4.77 (s, 2H), 4.52- 4.31 (m, 4H), 2.94-3.0 (m, 2H), 2.35 (t, 2H),1.74-1.82 (m, 4H).

Example 116a:(R)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one,or(S)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one

and

Example 116b:(S)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one,or(R)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one

Step A: 4-fluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-2-amine

Sodium hydride (5.48 g, 137 mmol) was added portion-wise to a solutionof tetrahydro-2H-pyran-4-ol (11.7 g, 114 mmol) in THF (150 mL) cooled to0° C. 4,6-Difluoropyrimidin-2-amine (15 g, 114 mmol) was added and themixture was stirred at RT for 12 h. The mixture was poured into waterand was extracted with ethyl acetate. The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. Purification by silica gel chromatography (0-20% EtOAcin petroleum ether) provided4-fluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-2-amine (10.5 g, 49mmol) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.18-6.91 (m, 2H),5.72-5.57 (m, 1H), 5.23-5.05 (m, 1H), 3.92-3.77 (m, 2H), 3.52-3.37 (m,2H), 2.06-1.88 (m, 2H), 1.66-1.51 (m, 2H).

Step B:9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one

A mixture of1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one(Intermediate D, 9.3 g, 28 mmol), DIEA (1.2 mL, 70 mmol) and4-fluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-2-amine (6.0 g, 28mmol) in EtOH (70 mL) was stirred at 80° C. for 12 h. After cooling toRT the mixture was diluted with water and extracted with EA. Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification bysilica gel chromatography (0-5% MeOH in DCM) provided9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one(10 g, 20 mmol) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.50-7.37(m, 1H), 7.30-7.17 (m, 1H), 6.97-6.84 (m, 1H), 6.08-5.90 (m, 2H),5.78-5.74 (m, 2H), 5.29-5.22 (m, 1H), 5.09 (d, 1H), 5.07-5.00 (m, 1H),4.27-3.97 (m, 3H), 3.85-3.75 (m, 2H), 3.43-3.36 (m, 2H), 2.94-2.79 (m,2H), 2.76-2.66 (m, 1H), 2.59 (m, 1H), 2.38-2.21 (m, 1H), 1.92-1.82 (m,3H), 1.80-1.63 (m, 2H), 1.54-1.47 (m, 2H), 1.39-1.20 (m, 1H); m/z=490.2

Step C:9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one

DAST (3.96 g, 24.6 mmol) was added to a stirred solution of9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one(6.0 g, 12 mmol) in DCM (60 mL) at 0° C. The mixture was allowed to warmto 25° C. and stir for one hour. The reaction mixture was poured intowater and extracted with DCM. The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purification by silica gel chromatography (0-5% MeOH in DCM)provided racemic9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one(5.8 g, 11.8 mmol) as a yellow solid. ¹H NMR (400 MHz, chloroform-d)δ=7.25-7.14 (m, 1H), 7.00-6.87 (m, 1H), 6.86-6.72 (m, 1H), 5.32-5.08 (m,3H), 4.69-4.44 (m, 2H), 4.32-4.10 (m, 2H), 3.99-3.89 (m, 2H), 3.61-3.49(m, 2H), 3.09-2.86 (m, 4H), 2.66-2.47 (m, 1H), 2.45-2.21 (m, 1H),2.07-1.95 (m, 3H), 1.81-1.65 (m, 5H); m/z=492.2 [M+H]⁺; t_(R)=0.48 min(LCMS method i). Chiral SFC (Chiralpak AD-3, 3 um, 4.6×50 mm, 35° C.;mobile phase A: CO₂, mobile phase B: 0.05% DEA in EtOH; isocraticelution, 40% B in A; flow rate: 3 mL/min; Detector: DAD) providedExample 116a (peak 1, 6.473 g; SFC t_(R)=1.54 min; m/z=492.2 [M+H]⁺) andExample 116b (peak 2, 5.998 g; SFC t_(R)=3.55 min; m/z=492.2 [M+H]⁺).

By employing similar methods as described for the preparation of Example116, using appropriate starting materials described herein, thefollowing compounds were prepared:

MS, m/z [M + H]⁺; t_(R), Ex Structure and Name method ¹H NMR 117

510.2; 1.57 min, LCMS method l ¹H NMR (300 MHz, DMSO- d₆) δ 7.42 (m,1H), 7.24 (brs, 1H), 6.93 (brs, 1H), 6.53 (brs, 2H), 6.32 (s, 1H), 5.25(d, 1H), 4.25 (brs, 2H), 2.9- 3.11 (m, 3H), 2.48-2.78 (m, 4H), 1.88 (t,2H), 1.32- 1.52 (m, 2H). 118

477.2; 1.99 min, LCMS method k ¹H NMR (300 MHz, DMSO- d₆) δ 8.15 (s,1H), 7.44 (m, 1H), 7.35-7.16 (m, 1H), 6.95 (s, 1H), 6.00 (s, 1H),5.42-5.12 (m, 2H), 4.21 (brs, 2H), 3.81 (dt, 2H), 3.55- 3.34 (m, 2H),3.14-2.88 (m, 3H), 2.58-2.7 (m, 2H), 1.8-1.95 (m, 4H), 1.38- 1.6 (m, 4H).

Example 119:1-(3,4-difluorophenyl)-4-fluoro-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A:1-(3,4-difluorophenyl)-4-hydroxy-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

To 125 mL of a thawed E. coli expressing cytochrome P450 3A4b5¹(80<OD₆₀₀<100) was added 375 mL of PSE buffer, 25 mL of sodium citrate(50 g/100 mL) and 200 mg of1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-onein 3 mL DMSO. The mixture was stirred in a 3 L plastic Erlenmeyer flaskequipped with 4 baffles and a breathable seal. 1-Octanol (50 μL) wasadded as antifoam agent. The mixture was stirred in an Infors HTMultitron shaker at 30° C. at 100 rpm for 5 h. The mixture was extractedwith 2×1 L EtOAc. The organic extracts were dried over MgSO₄, filtered,and concentrated to dryness to afford 600 mg of a blue solid. The crudematerial was dissolved into 4 mL DMSO and purified by preparative HPLC(Vario-Prep HPLC column VP 250/21 Nucleodur® 100-10 C18ec; mobile phaseA: water+0.1% HCOOH, mobile phase B: ACN+0.1% HCOOH; flow: 40 mL/min;gradient elution 0-70% B over 25 min, 70% B for 5 min).1-(3,4-difluorophenyl)-4-hydroxy-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-onewas isolated with a UV purity of 82%. The isolated material wassubjected to a second preparative HPLC purification (gradient elution20-60% B over 20 min, 60% B for 5 min) which provided1-(3,4-difluorophenyl)-4-hydroxy-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one(40.5 mg, 18.6% yield, >95% UV purity). ¹H NMR (600 MHz, DMSO-d₆) δ 8.21(d, J=0.9 Hz, 1H), 7.50-7.37 (m, 1H), 7.24 (s, 1H), 6.92 (s, 1H), 6.20(d, J=0.9 Hz, 1H), 5.10 (d, J=4.4 Hz, 1H), 4.93 (q, J=9.1 Hz, 2H), 4.24(s, 2H), 4.13 (dt, J=13.9, 7.1 Hz, 1H), 3.00 (t, J=13.2 Hz, 2H), 2.72(dd, J=17.1, 5.6 Hz, 1H), 2.61 (t, J=1.9 Hz, 1H), 2.36-2.28 (m, 1H),1.93 (d, J=13.3 Hz, 1H), 1.85 (d, 1H), 1.75 (s, 1H), 1.57 (t, 1H), 1.36(s, 1H); m/z=473.2 [M+H]⁺; t_(R)=0.63 min (LCMS method i) ¹ Preparationof the biocatalyst, please refer to: Recombinant Human Cytochrome P450Monooxygenases for Drug Metabolite Synthesis, Biotechnol Bioeng. 2010Aug. 1; 106(5):699-706. doi: 10.1002/bit.22775, and Recombinant Yeastand Bacteria that Express Human P450s: Bioreactors for Drug Discovery,Development, and Biotechnology Steven P. Hanlon, Thomas Friedberg, C.Roland Wolf, Oreste Ghisalba, Matthias Kittelmann Book Editors: Prof.Dr. Rolf D. Schmid, Dr. Vlada B. Urlacher; First published: 21 Jun.2007.

Step B:1-(3,4-difluorophenyl)-4-fluoro-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

In a 10 mL vial,1-(3,4-difluorophenyl)-4-hydroxy-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one (19 mg, 0.040 mmol) wasdissolved in DCM (0.40 mL), and DAST (11 μL, 0.080 mmol) in DCM wasadded at 0° C. After stirring for 10 min, the reaction mixture wasallowed to warm to RT and stir overnight. The mixture was quenched withsat. NaHCO₃, stirred 20 min, and extracted with EtOAc. The extracts werewashed with brine, dried over MgSO₄, filtered, and concentrated.Purification by reverse phase flash chromatography (RediSep® Rf Gold®Reversed Phase C18, 0-90% ACN in water). Product-containing fractionswere combined, frozen, and lyopholized to provide the title compound (10mg, 0.020 mmol). Note than any enantiomeric excess which may have beenintroduced during the CYP450 oxidation in Step A was not determined. ¹HNMR (400 MHz, methylene chloride-d2) δ 7.12 (dd, J=8.5, 4.3 Hz, 1H),6.93-6.82 (m, 1H), 6.82-6.69 (m, 1H), 5.81 (d, J=4.2 Hz, 1H), 5.20 (d,J=23.9 Hz, 1H), 4.66 (s, 2H), 4.19 (dd, J=27.7, 13.5 Hz, 2H), 3.12-2.66(m, 4H), 2.44 (dt, J=15.4, 7.8 Hz, 1H), 2.39-2.25 (m, 1H), 1.99-1.86 (m,1H), 1.69 (ddd, J=24.1, 10.9, 4.2 Hz, 3H), 1.53 (d, J=20.5 Hz, 1H);m/z=475.3 [M+H]⁺; t_(R)=0.65 min (LCMS method i).

Example 120:9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A: 2-amino-6-(1,1-difluoroethyl)pyrimidin-4-ol

A mixture of ethyl 4,4-difluoro-3-oxopentanoate (3.00 g, 16.6 mmol),guanidine hydrochloride (3.2 g, 33 mmol) and sodium ethoxide (2.7 g, 50mmol) in EtOH (40 mL) was heated at 80° C. for 5 h. The reaction mixturewas concentrated under reduced pressure and diluted with water andEtOAc. The organic layer was separated, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure to provide2-amino-6-(1,1-difluoroethyl)pyrimidin-4-ol as an off-white solid (5.4g). m/z=176.1 [M+H]⁺; t_(R)=0.87 min (LCMS method j).

Step B:9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 2-amino-6-(1,1-difluoroethyl)pyrimidin-4-ol (1.50 g, 7.75mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one(Intermediate A, 1.08 g, 3.87 mmol), PyBrop (5.40 g, 11.6 mmol) andtriethylamine (2.3 mL, 23 mmol) in dioxane (10 mL) was stirred at RT for12 h. The reaction mixture was poured into ice cold water and extractedtwice with EtOAc. The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. Purification by silica gel chromatography (EtOAc) provided thetitle compound (0.42 g). ¹H NMR (300 MHz, methanol-d4) δ 7.41 (m, 1H),7.29 (m, 1H), 7.09 (m, 1H), 6.28 (s, 2H), 6.12 (s, 1H), 4.31 (brs, 2H),2.91 (t, 2H), 2.41 (t, 2H), 2.20 (br s, 2H), 1.71-1.9 (m, 7H), 1.4-1.52(m, 2H); m/z=438.2 [M+H]⁺; t_(R)=0.61 min (LCMS method l).

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyloptionally substituted with one or more halo substituents; R² is H orfluoro; X¹ is CH₂ or O; R⁴ is a mono or bicyclic heteroaryl, optionallysubstituted with one or more R³ substituents; each R³ is independentlyselected from C₆₋₁₀aryl, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN,C(O)OC₁₋₆alkyl, OH, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5- to 10 memberedheteroaryl, 4-10 membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b),wherein R^(a) and R^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl; wherein said aryl,heterocyclyl, heteroaryl, C₃₋₇cycloalkyl, C₃₋₇cycloakenyl,C₃₋₇cycloalkoxy are further optionally substituted with one or moresubstituents independently selected from OH, CN, C₃₋₇cycloalkyl,C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl), halo, haloC₁₋₆alkyl,—C(O)—C₁₋₆alkyl, phenyl optionally further substituted with halo; andheteroaryl optionally substituted with halo, C₁₋₆alkyl, haloC₁₋₆alkyl orC₃₋₇cycloalkyl; R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,alkoxyC₁₋₆alkyl, C₃₋₇Cycloalkyl, C₃₋₇cycloalkenyl,C₃₋₇cycloalkylC₁₋₆alkyl, phenyl, benzyl, 4-10 membered heterocyclyl,5-10 membered heteroaryl; wherein phenyl, heterocyclyl andC₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆akenyl isoptionally substituted by one or more substituents selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyl optionally further substituted withhalo; heterocyclyl optionally further substituted with C₁₋₆alkyl orhaloC₁₋₆alkyl; with the proviso that when R² is F, then X¹ is CH₂. 2.The compound according the claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is selected from the group consisting ofpyrimidinyl, pyrazinyl, triazolyl, triazinyl, pyridinyl, pyridine oxide,pyrimidine oxide, pyrazine oxide, quinolinyl, quinazolinyl,quinoxalinyl, indazolyl, pyrazolopyrimidinyl, pyridopyrazinyl,triazolopyridazinyl, benzooxazolyl, oxadiazolyl, tetrazolyl,thiadiazolyl, oxazolyl, and thiazolyl, each of which is optionallysubstituted with one or more R³ substituents; each R³ is independentlyselected from C₆₋₁₀aryl, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN,C(O)OC₁₋₆alkyl, OH, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5- to 10 memberedheteroaryl, 4-10 membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b),wherein R^(a) and R^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl; wherein said aryl,heterocyclyl, heteroaryl, C₃₋₇cycloalkyl, C₃₋₇cycloakenyl,C₃₋₇cycloalkoxy are further optionally substituted with one or moresubstituents independently selected from OH, CN, C₃₋₇cycloalkyl,C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl), halo, haloC₁₋₆alkyl,—C(O)—C₁₋₆alkyl, phenyl optionally further substituted with halo; andheteroaryl optionally substituted with halo, C₁₋₆alkyl, haloC₁₋₆alkyl orC₃₋₇cycloalkyl; and wherein R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, alkoxyC₁₋₆alkyl, C₃₋₇Cycloalkyl, C₃₋₇cycloalkenyl,C₃₋₇cycloalkylC₁₋₆alkyl, phenyl, benzyl, 4-10 membered heterocyclyl,5-10 membered heteroaryl; wherein phenyl, heterocyclyl andC₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆akenyl isoptionally substituted by one or more substituents selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyl optionally further substituted withhalo; heterocyclyl optionally further substituted with C₁₋₆alkyl orhaloC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 3. Thecompound according to claim 1 or 2, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is selected from:

wherein the * depicts the point of attachment to the nitrogen of thespiropiperidinyl moiety; and wherein n is an integer between 1 and 3; pis 1 or 2, s is an integer between 1 and 4; and R^(3a), R^(3b) andR^(3c) are independently selected from the group consisting of H,C₆₋₁₀aryl, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN, C(O)OC₁₋₆alkyl, OH,C₃₋₇cycloalkyl, C₃₋₇Cycloalkenyl, 5- to 10 membered heteroaryl, 4-10membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b), wherein R^(a) andR^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl; wherein said aryl,heterocyclyl, heteroaryl, C₃₋₇cycloalkyl, C₃₋₇cycloakenyl,C₃₋₇cycloalkoxy are further optionally substituted with one or moresubstituents independently selected from OH, CN, C₃₋₇cycloalkyl,C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl), halo, haloC₁₋₆alkyl,—C(O)—C₁₋₆alkyl, phenyl optionally further substituted with halo; andheteroaryl optionally substituted with halo, C₁₋₆alkyl, haloC₁₋₆alkyl orC₃₋₇cycloalkyl; R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,alkoxyC₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl,C₃₋₇cycloalkylC₁₋₆alkyl, phenyl, benzyl, 4-10 membered heterocyclyl,5-10 membered heteroaryl; wherein phenyl, heterocyclyl andC₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆akenyl isoptionally substituted by one or more substituents selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyl optionally further substituted withhalo; heterocyclyl optionally further substituted with C₁₋₆alkyl orhaloC₁₋₆alkyl; and wherein R^(3d) is selected from H, C₆₋₁₀aryl,C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₆cycloalkyl, 5- or 6-membered heteroaryl;and wherein said aryl, cycloalkyl, heteroaryl are further optionallysubstituted with one or more substituents independently selected fromC₃₋₆cycloalkyl, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, halo andhaloC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to any one of claims 1 to 3 wherein the compound hasFormula (II); or a pharmaceutically acceptable salt thereof:

wherein R^(3a), R^(3b) and R^(3c) are independently selected from thegroup consisting of H, C₆₋₁₀aryl, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy,hydroxyC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN,C(O)OC₁₋₆alkyl, OH, C₃₋₇cycloalkyl, C₃₋₇Cycloalkenyl, 5- to 10 memberedheteroaryl, 4-10 membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b),wherein R^(a) and R^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl; wherein said aryl,heterocyclyl, heteroaryl, C₃₋₇cycloalkyl, C₃₋₇cycloakenyl,C₃₋₇cycloalkoxy are further optionally substituted with one or moresubstituents independently selected from OH, CN, C₃₋₇cycloalkyl,C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl), halo, haloC₁₋₆alkyl,—C(O)—C₁₋₆alkyl, phenyl optionally further substituted with halo; andheteroaryl optionally substituted with halo, C₁₋₆alkyl, haloC₁₋₆alkyl orC₃₋₇cycloalkyl; R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,alkoxyC₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl,C₃₋₇cycloalkylC₁₋₆alkyl, phenyl, benzyl, 4-10 membered heterocyclyl,5-10 membered heteroaryl; wherein phenyl, heterocyclyl andC₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆akenyl isoptionally substituted by one or more substituents selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyl optionally further substituted withhalo; heterocyclyl optionally further substituted with C₁₋₆alkyl orhaloC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 5. Thecompound according to claim 4, or a pharmaceutically acceptable saltthereof, wherein R^(3a) is H; NH₂ or hydroxyC₁₋₃alkyl; R^(3b) isselected from the group consisting of halo, C₁₋₆alkyl, haloC₁₋₆alkyl,C₃₋₇cycloalkyl, OR⁵, 4-10 membered heterocyclyl, 5- to 10-memberedheteroaryl, phenyl, and wherein said heterocyclyl, heteroaryl, phenyland cycloalkyl is further optionally substituted with one or moresubstituents independently selected from C₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, halo and haloC₁₋₆alkyl; wherein R⁵ is C₁₋₆alkyl,haloC₁₋₆alkyl, C₃₋₇cycloalkyl, phenyl, benzyl, 4-10 memberedheterocyclyl, 5-10 membered heteroaryl; wherein phenyl, heterocyclyl orC₃₋₇cycloakyl is optionally substituted by one or more substituentsindependently selected from C₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxy andhalo; and R^(3c) is H or halo.
 6. The compound according to any one ofclaims 1 to 3, wherein the compound has Formula (III); or apharmaceutically acceptable salt thereof:

wherein wherein Y¹ is N or CR^(3c); and wherein R^(3a), R^(3b) andR^(3c) are independently selected from the group consisting of H,C₆₋₁₀aryl, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN, C(O)OC₁₋₆alkyl, OH,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5- to 10 membered heteroaryl, 4-10membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b), wherein R^(a) andR^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl; wherein said aryl,heterocyclyl, heteroaryl, C₃₋₇cycloalkyl, C₃₋₇cycloakenyl,C₃₋₇cycloalkoxy are further optionally substituted with one or moresubstituents independently selected from OH, CN, C₃₋₇cycloalkyl,C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl), halo, haloC₁₋₆alkyl,—C(O)—C₁₋₆alkyl, phenyl optionally further substituted with halo; andheteroaryl optionally substituted with halo, C₁₋₆alkyl, haloC₁₋₆alkyl orC₃₋₇cycloalkyl; R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,alkoxyC₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl,C₃₋₇cycloalkylC₁₋₆alkyl, phenyl, benzyl, 4-10 membered heterocyclyl,5-10 membered heteroaryl; wherein phenyl, heterocyclyl andC₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆akenyl isoptionally substituted by one or more substituents selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyl optionally further substituted withhalo; heterocyclyl optionally further substituted with C₁₋₆alkyl orhaloC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 7. Thecompound according to any one of claims 1 to 3, wherein the compound hasFormula (IV); or a pharmaceutically acceptable salt thereof:

and wherein R¹ is as defined in Formula I, Y² is N or CR^(3b); andwherein R^(3a), R^(3b), R^(3c) and R^(3e) are independently selectedfrom H, C₆₋₁₀aryl, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN, C(O)OC₁₋₆alkyl, OH,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5- to 10 membered heteroaryl, 4-10membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b), wherein R^(a) andR^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇Cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl; wherein said aryl,heterocyclyl, heteroaryl, C₃₋₇cycloalkyl, C₃₋₇cycloakenyl,C₃₋₇cycloalkoxy are further optionally substituted with one or moresubstituents independently selected from OH, CN, C₃₋₇cycloalkyl,C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl), halo, haloC₁₋₆alkyl,—C(O)—C₁₋₆alkyl, phenyl optionally further substituted with halo; andheteroaryl optionally substituted with halo, C₁₋₆alkyl, haloC₁₋₆alkyl orC₃₋₇cycloalkyl; R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,alkoxyC₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl,C₃₋₇cycloalkylC₁₋₆alkyl, phenyl, benzyl, 4-10 membered heterocyclyl,5-10 membered heteroaryl; wherein phenyl, heterocyclyl andC₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆akenyl isoptionally substituted by one or more substituents selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyl optionally further substituted withhalo; heterocyclyl optionally further substituted with C₁₋₆alkyl orhaloC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 8. Thecompound according to any one of claims 1 to 3, wherein the compound hasFormula (V); or a pharmaceutically acceptable salt thereof:

wherein Y³ is N, NR^(3d) or CR^(3a); Y⁴ is N, NR^(3f) or CR^(3b); Y⁵ isN, NR^(3g) or CR^(3c); Y⁶ is N, NR^(3h) or CR^(3e); wherein R^(3a),R^(3b), R^(3c), R^(3e) are independently selected from H, C₆₋₁₀aryl,benzyl, C₁₋₆alkyl, C₃₋₇cycloalkoxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, halo, haloC₁₋₆alkyl, OR⁵, CN, C(O)OC₁₋₆alkyl, OH,C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5- to 10 membered heteroaryl, 4-10membered heterocyclyl, —C(O)NH₂, and NR^(a)R^(b), wherein R^(a) andR^(b) are independently H, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇Cycloalkyl-C₁₋₆alkyl or halo C₁₋₆alkyl; wherein said aryl,heterocyclyl, heteroaryl, C₃₋₇cycloalkyl, C₃₋₇cycloakenyl,C₃₋₇cycloalkoxy are further optionally substituted with one or moresubstituents independently selected from OH, CN, C₃₋₇cycloalkyl,C₃₋₇cycloalkoxy, NH₂, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,hydroxyC1-6alkyl, —S—C₁₋₆alkyl; —S-(haloC₁₋₆alkyl), halo, haloC₁₋₆alkyl,—C(O)—C₁₋₆alkyl, phenyl optionally further substituted with halo; andheteroaryl optionally substituted with halo, C₁₋₆alkyl, haloC₁₋₆alkyl orC₃₋₇cycloalkyl; R⁵ is C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,alkoxyC₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl,C₃₋₇cycloalkylC₁₋₆alkyl, phenyl, benzyl, 4-10 membered heterocyclyl,5-10 membered heteroaryl; wherein phenyl, heterocyclyl andC₃₋₇cycloakyl, C₃₋₇cycloalkylC₁₋₆alkyl, C₃₋₇cycloalkylC₁₋₆akenyl isoptionally substituted by one or more substituents selected fromC₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyl optionally further substituted withhalo; heterocyclyl optionally further substituted with C₁₋₆alkyl orhaloC₁₋₆alkyl; wherein R^(3d), R^(3f), R^(3g), R^(3h) are independentlyselected from H, C₆₋₁₀aryl, C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₆cycloalkyl, 5-or 6-membered heteroaryl; and wherein said aryl, heteroaryl,C₃₋₆cycloalkyl are further optionally substituted with one or moresubstituents independently selected from C₃₋₆cycloalkyl, C₁₋₆alkyl,C₁₋₆alkoxy, haloC₁₋₆alkoxy, halo and haloC₁₋₆alkyl; or apharmaceutically acceptable salt thereof.
 9. The compound according toclaim 8, or a pharmaceutically acceptable salt thereof, wherein themoiety:

is selected from the following:

wherein R^(3a), R^(3b), R^(3c), R^(4e) and R^(4f) are as defined inclaim 8 and wherein * depicts the point of attachment to the nitrogen ofthe spiropiperidinyl moiety.
 10. The compound according to any one ofthe preceding claims, or a pharmaceutically acceptable salt thereof,wherein R¹ is phenyl optionally substituted with one or twosubstitutents independently selected from F and Cl.
 11. The compoundaccording to any one of the preceding claims, or a pharmaceuticallyacceptable salt thereof, wherein X¹ is CH₂ and R² is F or H.
 12. Thecompound according to any one of the preceding claims, or apharmaceutically acceptable salt thereof, wherein X¹ is O and R² is H.13. The compound according to claim 1, wherein the compound is selectedfrom:1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(6-(trifluoromethyl)benzo[d]oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(4-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine1-oxide;9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(2-(3,3-dimethylazetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-((1R,2R/1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(6-hydroxy-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-cyclopentyl-1,2,4-triazin-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one1-(4-chloro-3-fluorophenyl)-9-(4-(trifluoromethyl)pyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(7-(trifluoromethyl)quinazolin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-(4-fluorophenyl)oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(2-phenyl-2H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-cyclohexyloxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)azetidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-(pyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-phenyl-1,3,4-oxadiazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine1-oxide;4-(3-chlorophenoxy)-2-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)pyridine1-oxide;9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(4-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(4-(4-amino-4-(trifluoromethyl)piperidin-1-yl)pyrimidin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-5-fluoro-6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(6-amino-2-(3-hydroxy-3-methylazetidin-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(6-(1,4-oxazepan-4-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;rac-9-(2-amino-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(2-methyl-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(1H-pyrazol-1-yl)pyrimidine-2-carbonitrile;1-(3,4-difluorophenyl)-9-(2-methoxy-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(6-(1H-pyrazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(2-morpholino-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(2-(dimethylamino)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(6-(4-chloro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-5-fluoro-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(4-amino-6-(4-fluoro-1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(6-(oxetan-3-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(6-(oxazol-2-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(6-amino-2-(pyridin-2-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one;1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one;Synthesis1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one;rac-1-(3,4-difluorophenyl)-9-(2-(1-hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecane-2-one;4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carboxamide;9-(2-chloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;(R)-9-(2-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;(S)-9-(2-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;(R)-9-(4-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(6-(4-fluoro-1H-pyrazol-1-yl)-2-morpholinopyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(4,4-difluorocyclohex-1-en-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(4-fluorophenyl-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one;9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one;9-(2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(2-(hydroxynethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecane-2-one;1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(4-chloro-3-fluorophenyl)-9-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(4-propoxypyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;rac-1-(3,4-difluorophenyl)-9-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-chloro-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;(S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;(R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;(R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;(S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(3,3-difluorocyclobutoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(2,2,2-trifluoroethoxy-1,1-d2)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-isopropoxypyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(2-hydroxyethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;rac-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;rac-9-(2-amino-6-(2,2,2-trifluoro-1-(3-methyloxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;rac-9-(2-amino-6-((4,4-difluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;rac-9-(2-amino-6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;(R)-9-(2-amino-6-((tetrahydro-2H-pyran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;rac-9-(2-amino-6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;rac-9-(2-amino-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;rac-9-(2-amino-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;rac-1-(3,4-difluorophenyl)-9-(6-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-2-(hydroxymethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;rac-1-(3,4-difluorophenyl)-9-(6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(hydroxymethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;(S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;(S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;(R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;(R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;(S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;rac ethyl4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-yl)-6-(((3S,4S)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate;(R)-9-(2-amino-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;(R)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;(S)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;(S)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;(R)-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;rac-9-(2-amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;rac-1-(3,4-difluorophenyl)-4-fluoro-9-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;and1-(3,4-difluorophenyl)-4-fluoro-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;or a pharmaceutically acceptable salt thereof.
 14. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein the compound is selected from the group consisting of:1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one;(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one,(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;and9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one.15. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to any one of claims 1 to 14 and one ormore pharmaceutically acceptable carriers.
 16. A combination comprisinga therapeutically effective amount of a compound according to any one ofclaims 1 to 14 or a pharmaceutically acceptable salt thereof, and one ormore therapeutic agents.
 17. A combination according to claim 16 whereinone or more therapeutic agents are independently selected from steroid;corticosteroids; glucocorticosteroids; non-steroidal glucocorticoidreceptor agonists; leukotriene receptor antagonists (LTRAs) includingLTB4 antagonists, LTD4 antagonists, Leukotriene A4 hydrolase (LTA4H)inhibitors, Cysteinyl-Leukotriene Receptor antagonists (includingMontelukast, Pranlukast, Zafirlukast); a modulator of prostaglandinpathway (e.g. CRTH2/DP2 receptor antagonist); Bruton's tyrosine Kinaseinhibitors (BTK inhibitors); PDE4 inhibitors; antihistamines; histamineH4 receptor antagonist; H1 receptor antagonists; beta-adrenergic drugssuch as beta (β)-2-adrenoceptor agonists; anticholinergic drugs or andanticholinergic or antimuscarinic agents (e.g. M2 and/or M3antagonists); nonsteroidal anti-inflammatory drugs (“NSAIDs”);analgesics; inhibitors of 5-lipoxygenase; inhibitors of FLAP(5-lipoxygenase activting protein); COX-2 selective inhibitors andstatins.
 18. A combination according to claim 16 comprising atherapeutically effective amount of a compound according to any one ofclaims 1 to 14 or a pharmaceutically acceptable salt thereof, and aleukotriene A4 hydrolase inhibitor selected from the group consisting of(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoicacid;(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoicacid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoicacid; and(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoicacid; or pharmaceutically acceptable salt thereof.
 19. A method ofmodulating LTC4S activity in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount of thecompound according to any one of claims 1 to 14 or a pharmaceuticallyacceptable salt thereof.
 20. A method of inhibiting LTC4S activity in asubject, wherein the method comprises administering to the subject atherapeutically effective amount of the compound according to any one ofclaims 1 to 14 or a pharmaceutically acceptable salt thereof.
 21. Amethod of treating a disorder selected from allergic disorders, asthma,childhood wheezing, chronic obstructive pulmonary disease, aspirinexacerbated respiratory disease, bronchopulmonary dysplasia, cysticfibrosis, interstitial lung disease (e.g. sarcoidosis, pulmonaryfibrosis, scleroderma lung disease, and usual interstitial inpneumonia), ear nose and throat diseases (e.g. sinusitis, rhinitis,nasal polyposis, rhinosinusitis, otitis media, and allergic eosinophilicesophagitis), eye diseases (e.g. conjunctivitis and giant papillaryconjunctivitis), skin diseases (e.g. psoriasis, atopic dermatitis,eczema and chronic urticaria), rheumatic diseases (e.g. rheumatoidarthritis, arthrosis, psoriasis arthritis, osteoarthritis, systemiclupus erythematosus, systemic sclerosis), vasculitis (e.g.Henoch-Schonlein purpura, Loffler's syndrome and Kawasaki disease),cardiovascular diseases (e.g. atherosclerosis, cerebrovascular diseases,acute ischemic heart attacks and post-heart attack treatment),gastrointestinal diseases (e.g. eosinophilic diseases in thegastrointestinal system, inflammatory bowel disease, irritable bowelsyndrome, colitis, celiaci and gastric haemorrhagia), urologic diseases(e.g. glomerulonephritis, interstitial cystitis, nephritis, nephropathy,nephrotic syndrome, hepatorenal syndrome, and nephrotoxicity), diseasesof the central nervous system (e.g. cerebral ischemia, spinal cordinjury, migraine, multiple sclerosis, and sleep-disordered breathing),endocrine diseases (e.g. autoimmune thyreoiditis, diabetes-relatedinflammation), urticaria, anaphylaxis, angioedema, oedema inKwashiorkor, dysmenorrhoea, burn-induced oxidative injury, multipletrauma, pain (inflammatory and neuropathic), endotoxin shock, sepsis,bacterial infections (e.g. from Helicobacter pylori, Pseudomonasaerugiosa or Shigella dysenteriae), fungal infections (e.g. vulvovaginalcandidasis), viral infections (e.g. hepatitis, meningitis, parainfluenzaand respiratory syncytial virus), hypereosinofilic syndrome, andmalignancies (e.g. Hodgkin's lymphoma, leukemia (e.g. eosinophilleukemia and chronic myelogenous leukemia), mastocytos, polycytemi vera,and ovarian carcinoma) wherein the method comprises administering to thesubject a therapeutically effective amount of the compound according toany one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.22. A compound of selected from the group consisting of:

wherein PG is a nitrogen protecting group; and PG² is a carboxylic acidprotecting group; PG³ is carbobenzyloxy (Cbz) or tert-butoxycarbonyl(BOC); each R^(1a) is halo, each R^(1b) is independently selected from Fand Cl; v is 1-3, and R¹ is phenyl optionally substituted with one, twoor three halo substituents.